Cognitive profile of patients with manganese-methcathinone encephalopathy

Neurotoxicology 76 (2020) 138–143

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Full Length Article

Cognitive profile of patients with manganese-methcathinone encephalopathy

T

Margus Ennoka,b,*, Katrin Sikka,c, Sulev Haldrea,b, Pille Tabaa,b a

Department of Neurology and Neurosurgery, Institute of Clinical Medicine, University of Tartu, L. Puusepa 8, 50406 Tartu, Estonia Neurology Clinic, Tartu University Hospital, L. Puusepa 8, 50406 Tartu, Estonia c Department of Neurology, Internal Medicine Clinic, North Estonia Medical Centre Foundation, J. Sütiste 19, 13419 Tallinn, Estonia b

A R T I C LE I N FO

A B S T R A C T

Keywords: Manganese Drug addiction Neuropsychological Cognitive profile

Manganese-methcathinone encephalopathy (MME) is a rare parkinsonian syndrome described in drug addicts who have self-injected a home-made mixture containing methcathinone and manganese. We assessed 14 patients with MME and compared their results with 14 matched control subjects. The patients had a parkinsonian syndrome with symmetrical bradykinesia, dystonias, and postural, gait and speech impairment, with moderate restrictions in activities of daily living. Their cognitive status was assessed with the Russian version of the Wechsler Adult Intelligence Scale (WAIS) and with tests of attention (Trail Making Test, Bourdon-Wiersma Dot Cancellation Test), memory (Auditory Verbal Learning Test, Rey-Osterrieth Complex Figure), motor skills (Grooved Pegboard), visuospatial skills (Money Road Map Test, Benton Judgment of Line Orientation), and executive abilities (Verbal Fluency, 5-Point Test, Wisconsin Card Sorting Test). Only a few significant differences emerged. After controlling for multiple comparisons, the results in the WAIS Object Assembly subtest, the Grooved Pegboard test (dominant and nondominant hand) and the Verbal Fluency test remained significant.

1. Introduction During the past two decades, neurologists in Estonia started to see cases of young patients with a distinct syndrome characterized by parkinsonism, dystonias, and falls (Sikk et al., 2007, 2013). The detailed history revealed that these patients appeared to be drug addicts injecting a home-made psychostimulant containing methcathinone (ephedrone) and manganese that was known by street names such as “cat,” “jeff” or “mul’ka.” Similar cases had already been described by Russian physicians in the 1980s and 1990s (Lukacher et al., 1987), and the condition was first termed “ephedrone encephalopathy” (Levin, 2005). Later analysis suggested that the probable cause of the parkinsonian syndrome is poisoning by manganese, which is a toxic by-product of the chemical reaction. Methcathinone may also have a role in the development of the neurological disorder (Sikk et al., 2011); therefore, the term manganese-methcathinone encephalopathy (MME) is used as a more precise description of this condition. There are no official diagnostic criteria for this condition. Diagnosis is based on anamnesis and clinical assessments. The mixture is prepared from over-the-counter medicines containing pseudoephedrine (Sikk et al., 2007). Subjects experience a

feeling of “rush,” with elevated mood, increased excitability, and alertness that has no direction and is unproductive (Lukacher et al., 1987). Strong psychological dependency develops quickly, and, after some months or years of drug use, neurological symptoms emerge (Selikhova et al., 2008). Most cases of this condition are described in various Eastern European countries – Russia (Levin, 2005), Ukraine (Sanotsky et al., 2007; Selikhova et al., 2008), Georgia (Rusz et al., 2014), Latvia (Stepens et al., 2008, 2014), Estonia (Sikk et al., 2010, 2013), Poland (Dolgan et al., 2015; Janocha-Litwin et al., 2015), and also in Turkey (Koksal et al., 2014; Varlibas et al., 2009; Yildirim et al., 2009). Occasional cases have been reported in Canada (de Bie et al., 2007), Italy (Colosimo and Guidi, 2009), and Ireland (Iqbal et al., 2012) among immigrants from Eastern Europe. In Estonia, the use of this substance has always been restricted to a tiny group of drug abusers, and the National Institute for Health Development in Estonia has discontinued monitoring it separately in statistical surveys about drug use. The development of symptoms varies widely, but the first neurological signs are usually noted 3–14 months after regular drug use begins. The condition is slowly progressive, and neurological status can worsen even after cessation of use of the drug. The most typical symptoms are postural instability, falls, gait disturbances (“cock walk”), hypokinesia,

⁎ Corresponding author at: Department of Neurology and Neurosurgery, Institute of Clinical Medicine, University of Tartu, L. Puusepa 8-H559, 50406 Tartu, Estonia. E-mail address: [email protected] (M. Ennok).

https://doi.org/10.1016/j.neuro.2019.10.007 Received 10 March 2019; Received in revised form 16 October 2019; Accepted 17 October 2019 Available online 31 October 2019 0161-813X/ © 2019 Published by Elsevier B.V.

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Table 1 Demographic and clinical characteristics of the patients. Case

Age

Sex

Education (years)

Age at start

Time of exposure (years)

HIV / Hep C

UPDRS total

UPDRS motor

SE

HY

MMSE

1 2 3 4 5 6 7 8 9 10 11 12 13 14

18 30 36 33 44 32 44 42 30 33 24 29 37 31

F M M M M M M F M M M M M M

9 8 8 7 8 9 11 10 10 8 9 12 15 13

14 27 19 24 34 27 26 27 28 19 22 27 28 26

2 1 8 9 8 1 10 7 2 13 1.5 2 4 4.5

+/+ +/+ –/+ –/+ +/+ +/+ –/+ –/+ –/+ +/+ –/+ –/+ –/+ +/+

23 35 59 79 27 26 68 51 42 50 16 42 41

14 19 41 49 21 15 45 34 21 30 7 33 25

80 90 50 55 90 85 70 60 80 70 90 80 70

3 2 4 4 2.5 3 3 3 2.5 3 2 3 3

30 30 30 28 28 30 30 28 30 28 30 30 29 29

Sex: M – male, F – female, HIV – human immunodeficiency virus, Hep C – hepatitis C, UPDRS – Unified Parkonson’s Disease Rating Scale, SE – Schwab-England Rating Scale, HY – Hoehn and Yahr staging, MMSE – Mini-Mental State examination.

Previous knowledge of the harmful effects of manganese on cognitive abilities results from studies of occupational and environmental exposure. Many papers in the last decades have reported defects in motor abilities and various cognitive domains that were associated with manganese (e.g. Al-Lozi et al., 2017; Bouchard et al., 2006; Bowler et al., 2006, 2007a, 2007b; Ellingsen et al., 2008; Klos et al., 2006; Kornblith et al., 2018; Laohaudomchok et al., 2011). However, no consistent profile of cognitive defects has emerged, and the differences may not be of clinical significance (Summers et al., 2011). Also, metaanalytic studies have suggested that neuropsychological performance in these studies can be accounted for by demographic variables, leaving the role of manganese in question (Greiffenstein and Lees-Haley, 2007; Lees-Haley et al., 2006). Due to improved occupational safety regulations, workers nowadays are exposed to significantly lower doses of manganese compared to those in earlier studies in mining and factory workers and also compared to patients with MME. Still, there are no comparative studies between inhalation and intravenous manganese exposure models in humans, thus it is not possible to provide exact estimate on toxicity. The aim of this study is to describe the cognitive status of patients with manganese-methcathinone exposure caused by drug abuse. We also examined the associations between clinical status and cognitive dysfunction in these patients.

dystonias, hypomimia, hypophonia, and dysarthria (Sikk et al., 2013). The most severe cases may be wheelchair-bound and may have lost their voices completely. Some studies also report psychiatric complications like depression, apathy, emotional lability, and behavioral disorders (Levin, 2005; Sanotsky et al., 2007; Selikhova et al., 2008; Yildirim et al., 2009). The probable cause of the symptoms is poisoning by manganese, a reaction by-product from potassium permanganate. It is estimated that drug users are exposed to a daily load of 60–180 mg of manganese, which is about 2000 times higher than the recommended healthy exposure (Sikk et al., 2007, 2011). Brain imaging of active methcathinone users shows hyperintensities in T1-weighted images in basal ganglia (Juurmaa et al., 2016; Sikk et al., 2010). Only two published studies are available in which the cognitive status of patients with this condition is investigated in detail. Levin (2005) assessed the cognitive status of 21 patients with MME. He noted deficits in various cognitive areas in these patients, including domains of attention (especially fast-developing weariness and lowered performance capacity), memory (in the activity and selectivity of remembering and recall), executive functions (tendency for perseverative responses), and general dullness of thinking (bradyphrenia). In the majority of the patients, these deficits were expressed at moderate (52.4% of study subjects; defined as test results in between −1.5 to −2 SD below suggested age norms in at least 2 cognitive domains) or mild levels (38.1% of study subjects; defined as test results up to −1.5 SD below suggested age norms in at least 2 cognitive domains). This indicates a wide variability in the cognitive presentation of these patients. In a more recent study, Koksal et al. (2014) reported the cognitive status of 9 patients, comparing the results with a matched control group. Patients fared worse in tests of working memory, nonverbal learning, verbal and nonverbal recall and recognition, and complex attentional abilities. However, no significant differences were found in constructional skills, fluency, mental control, and verbal conceptual abilities. Case series studies or case descriptions do not report notable cognitive deficits (de Bie et al., 2007; Iqbal et al., 2012; Sikk et al., 2007; Stepens et al., 2008), or only mild deficits in executive abilities or memory are pointed out (Colosimo and Guidi, 2009; Sanotsky et al., 2007; Selikhova et al., 2008; Yildirim et al., 2009). Still, in these case studies the evaluation is mostly based on a clinical impression or on data generated using simple screening tests, mainly the Mini Mental State Examination (MMSE; Folstein et al., 1975), which may not be clinically sensitive to cognitive deficits in a younger cohort, particularly when the cognitive changes manifest at mild levels. Therefore, the possibility of cognitive dysfunction in these patients cannot be ruled out.

2. Methods 2.1. Study sample We assessed 14 patients (12 men, 2 women) with a mean age of 33.1 (SD = 7.3) years and a mean education of 9.8 (SD = 2.3) school years. All patients were interviewed about their drug use history. All had used methcathinone regularly with a mean duration of 5.2 years (range 1–13 years), and nearly half of the subjects (6–8 patients) were active users at the time of testing. Some subjects noted an occasional use of other drugs (mainly amphetamine or heroin) but reported that methcathinone was their preferred substance. One patient had a history of head trauma; others had no previous neurological conditions. All patients were positive for hepatitis C virus (HCV), and 6 were human immunodeficiency virus (HIV) positive. Their general ability level was normal (mean MMSE score 29.3, range 28–30). Further details of the sample are shown in Table 1. The patients were compared with 14 demographically matched controls (12 men, 2 women) with a mean age of 33.6 (SD = 7.1) years and mean education of 9.6 (SD = 2.2) school years. All subjects in the control group were in good health and had no history of neurological disorders or substance abuse. The control group came from a prison 139

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Table 2 WAIS test results. Patients

Information Comprehension Arithmetic Similarities Digit Span Vocabulary Digit-Symbol Picture Completion Block Design Picture Arrangement Object Assembly VIQ PIQ FSIQ

Controls

M

SD

Median

Min/Max

M

SD

Median

Min/Max

U

Z

p

r

10 8.43 9 8.79 9.43 10.79 6.86 11.21 10.43 8.57 8.86 96.29 96.93 96.36

3.14 2.47 2.39 3.12 3.06 1.89 1.7 2.33 2.28 1.45 1.46 11.07 8.58 9.47

10 8 8 9.5 9.5 11 7 11 10 8.5 9 98 99.5 94.5

5/14 5/14 6/13 1/12 6/16 8/14 4/10 8/16 7/14 6/11 6/11 75/113 85/110 79/111

10.57 10.5 9.71 10.14 8.64 11.64 8.86 11.21 12.07 9.29 11.64 101.0 106.43 103.5

3.57 2.14 2.37 2.66 2.56 1.74 1.92 2.52 2.59 1.77 2.56 12.3 9.94 10.85

11.5 10 10 10 9 11.5 9 11 12 9.5 11 103.5 103.5 104.5

3/17 8/16 6/13 3/14 4/14 9/15 5/14 6/16 7/16 6/12 8/18 81/124 95/123 87/125

90 49 81 72.5 86 73 40.5 92.5 62 73.5 29 73.5 53.5 65.5

−0.37 −2.276 −0.789 −1.196 0.562 −1.173 −2.684 −0.258 −1.679 −1.145 −3.255 −1.127 −2.049 −1.496

0.711 0.023* 0.43 0.232 0.574 0.241 0.007** 0.796 0.093 0.252 0.001** 0.26 0.04* 0.135

−0.07 −0.43 −0.15 −0.23 0.11 −0.22 −0.51 −0.05 −0.32 −0.22 −0.62 −0.21 −0.39 −0.28

* Significant at the p < 0.05 level. ** Significant at the p < 0.01 level.

assessed with the Money Standardized Road Map Test (Money, 1976) and the Benton Judgment of Line Orientation (Benton et al., 1994). Executive functions were assessed with the Verbal Fluency Test (animal naming; Gladsjo et al., 1999), the 5-Point Test (Regard et al., 1982), and the Wisconsin Card Sorting Test (Heaton et al., 1993).

population, and in this way both groups were also similar in terms of socio-economic context. Further, this insured that subjects in the control group had undergone an overall medical examination, were healthy, and had no access to any drugs or addictive substances. None of the control subjects were sentenced for drug-related offences. All subjects in both groups were right-hand-dominant. The study was approved by the Ethics Review Committee on Human Research of the University of Tartu. Testing of control subjects was performed in agreement with the Prisons Department of the Ministry of Justice of the Republic of Estonia.

2.3. Data analysis For descriptive statistics, we calculated and reported the means, standard deviations, medians and minimum/maximum. Since the study sample was limited and not all of the data from the test results met the normality assumption, a non-parametric Mann-Whitney U test was used to compare the groups. Effect sizes (r) were calculated by dividing the respective Z value by the square root of the sample size, and, for interpretation, suggested standard values of 0.1 for small, 0.3 for medium and 0.5 for large effect were used (Fritz et al., 2012). To estimate possible associations between cognitive measures and clinical scales, the Spearman rank correlation was computed. The data analysis package Statistica (Dell, 2016) was used for the analysis.

2.2. Measures Clinical examination was performed by neurologists using the Unified Parkinson’s Disease Rating Scale (UPDRS; Fahn et al., 1987), the Schwab-England Rating Scale (SE; Schwab and England, 1969) and Hoehn and Yahr staging (HY; Hoehn and Yahr, 1967). UPDRS is the most widely used standardized scale to assess Parkinsonism. It is designed to monitor patients’ disability and impairment. Parts I (mentation, behavior and mood), II (activities of daily living; ADL), and III (motor examination) contain 44 questions, each measured on a 5-point scale (0–4). The total UPDRS score is the combined sum of parts I, II and III: 0 (not affected) to 176 (severely affected). Part IV (complications of therapy) was not administered. The SE and HY rating scales are widely used measures for daily living activities and disease staging. In SE, the patients’ condition is scored on a scale from 100% (completely independent) to 0% (completely dependent), and in HY from 1 (unilateral involvement of the body) to 5 (wheelchair-bound or bedridden). To assess neuropsychological status, all subjects were examined using a complex battery of tests assessing intellectual functions, attention, memory, executive functions, and visuospatial and motor abilities. General intellectual functioning was assessed with the Russian version (Filimonenko and Timofeev, 2002) of the Wechsler Adult Intelligence Scale (WAIS; Wechsler, 1955). The following subtests were included: Information, Comprehension, Arithmetic, Similarities, Digit Span, Vocabulary in the Verbal Scale, Digit-Symbol Coding, Picture Completion, Block Design, Picture Arrangement, and Object Assembly in the Nonverbal Scale. Although WAIS has been updated to a newer version, this is the most current version available in the Russian language. Attention was assessed with the Trail Making Test (Reitan, 1955) and the Bourdon-Wiersma Dot Cancellation Test (Hänninen and Lindström, 1979). Memory was assessed with the Auditory Verbal Learning Test (Boake, 2000; Rey, 1964) and the Rey-Osterrieth Complex Figure Test (Osterrieth, 1993; Rey, 1993). Motor performance was assessed with the Grooved Pegboard Test (Kløve, 1963). Visuospatial functions were

3. Results The average total UPDRS score of patients was 43.0 ± 18.3, and the mean score of part III (Motor Examination) was 27.2 ± 12.7. In the context of Parkinson`s disease, these motor scores would suggest a mild to severe disease (Goetz et al., 2012; Martínez-Martín et al., 2014). The most prevalent symptoms were symmetrical bradykinesia, dystonias, and early postural, gait, and speech impairment. The mean value of HY staging was 2.9 ± 0.6; the largest number of patients (n = 7) were categorised as stage 3, indicating bilateral disease with postural instability and moderate effect on ADL. The average score of SE ADL was 74.6 ± 13.5%, indicating that patients were not completely independent; they needed some assistance, and some chores were more difficult or took two to three times as long to perform. The general intellectual ability level was in the average range in both groups. WAIS test data are provided in Table 2. When comparing the results of intelligence scale scores, a significant difference was observed in the performance IQ but not in the verbal IQ or full-scale IQ. When comparing the results of different WAIS subtests, the control group outperformed patients in Comprehension, Digit-Symbol Coding, and Object Assembly subtests. The results of the neuropsychological tests are provided in Table 3. When comparing the results in tests of attentional processes, a significant difference was observed in the Bourdon-Wiersma average row time. This test requires subjects to scan rows of groups of dots with 3, 4, 140

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Table 3 Results of neuropsychological tests. Patients

Trails A Trails B B-W average speed B-W omissions B-W comissions Grooved pegboard dominant Grooved pegboard nondominant AVLT learning AVLT immediate AVLT delayed AVLT recognition A AVLT recognition accuracy ROCF copy ROCF immediate ROCF delayed Money JOLO 5-point designs 5-point repetitions Animal naming Animal naming repetitions WCST categories completed WCST fail to maintain WCST conceptual level % WCST perseverative responses % WCST perseverative errors % WCST nonperseverative –errors %

Controls

M

SD

Median

Min /Max

M

SD

Median

Min /Max

U

Z

P

r

40.57 105.14 16.96 20.21 0.57 146.36 154.64 48.71 9.29 9.07 12.21 37.57 27.96 15.18 14.11 29 25.07 26.64 0.93 15.29 0.36 4 0.71 47.66 25.21 22.59 16.47

12.29 37.21 4.75 19.79 1.09 80.49 74.86 7.8 2.95 3.1 2.19 3.88 4.23 6.71 5.9 3.4 4.03 10.07 1 4.39 0.63 2.11 0.83 21.68 9.76 8.14 9.27

39 90 15.58 12 0 114 137.5 49 8.5 9.5 12 38 28 15.25 14.5 30 25.5 26 1 15 0 5 0.5 47.08 24.22 22.66 17.42

22/63 69/197 12.6/30.4 3/67 0/4 68/300 73/300 36/62 5/15 4/14 8/15 30/44 16.5/33 4.5/26 4/25 21/32 15/30 14/44 0/3 9/26 0/2 0/6 0/2 8.59/84.21 7.89/40.62 7.89/33.59 3.80/39.06

36.5 93.93 12.67 16.36 0.43 69.5 75.29 54.43 11.64 11.14 14.21 39.14 29 20.93 20.43 28.21 26.71 29.64 0.71 21.64 0.14 4.57 1.36 60.71 17.47 15.61 15.14

17.43 37.03 2.32 18.81 0.76 10.6 11.5 6.09 2.47 2.82 0.97 2.91 3.65 4.79 5.64 4.44 2.55 10.61 1.07 5.34 0.36 2.14 1.34 21.04 8.2 7.54 11.17

28.5 94.5 12.45 7 0 67.5 72 54 12.5 11.5 14.5 38.5 29.5 20 18.75 29.5 27 30 0 20.5 0 6 1 69.67 15.49 13.02 11.69

19/74 48/156 10.0/19.1 2/56 0/2 59/99 62/99 44/67 8/15 6/14 12/15 34/44 21.5/34 13.5/29 12/29.5 17/32 22/30 14/48 0/3 15/35 0/1 0/6 0/4 17.19/84.0 8.0/32.28 7.62/29.69 4.0/40.62

64.5 82.5 29 78 93 16.5 18 57 50.5 62.5 43 76.5 90 51.5 42.5 91.5 75.5 81.5 83 27.5 83 75.5 72 67 53.5 51.5 79.5

1.543 0.712 3.171 0.921 0.279 3.747 3.678 −1.89 −2.197 −1.65 −2.606 −0.995 −0.371 −2.139 −2.554 0.304 −1.043 −0.759 0.747 −3.248 0.965 −1.11 −1.262 −1.425 2.045 2.137 0.85

0.123 0.476 0.002** 0.357 0.78 0.0002** 0.0002** 0.059 0.028* 0.099 0.009** 0.32 0.711 0.032* 0.011* 0.761 0.297 0.448 0.455 0.001** 0.334 0.267 0.207 0.154 0.041* 0.033* 0.395

0.29 0.13 0.60 0.17 0.05 0.71 0.70 −0.36 −0.42 −0.31 −0.49 −0.19 −0.07 −0.40 −0.48 0.06 −0.20 −0.14 0.14 −0.61 0.18 −0.21 −0.24 −0.27 0.39 0.40 0.16

B-W – Bourdon-Wiersma Dot Cancellation Test, AVLT – Auditory Verbal learning Test, ROCF – Rey-Osterrieth Complex Figure, JOLO – Judgment of Line Orientation, WCST – Wisconsin Card Sorting test. * Significant at the p < 0.05 level. ** Significant at the p < 0.01 level.

As expected, the test of motor proficiency, the Grooved Pegboard, was the most difficult for patients to perform. Two patients were unable to perform the test in either hand, and a score of 300 s was assigned as their result to include them in the analysis. Compared to the control group, the patients took, on average, 77 s more for the dominant hand and 79 s more for the nondominant hand to perform the test. Usually, both hands were equally influenced by the motor deficit. The mean difference between hands was 8.3 s with a trend of the dominant hand being better. Only three patients had a difference between hands greater than 45 s (for two of them the dominant hand was better, and for one the nondominant hand was better). To sum up the results, we observed some deficits in several cognitive tests that assess motor ability, concentration, memory, and executive skills. When applying the Bonferroni correction due to multiple comparisons (p < .00125), only the differences in WAIS Object Assembly, Grooved Pegboard dominant and nondominant hand, and Verbal Fluency remained significant. Since the duration of patients’ drug abuse varied from 1 to 13 years, we estimated the dose-response relationships to cognitive tests. We calculated the Spearman rank correlation between time of exposure and cognitive test results. None of the correlations proved significant, but AVLT learning showed a trend (r = 0.52, p < .055). We then looked at possible correlations with cognitive status, activities of daily living, and clinical disability scales. The correlations of UPDRS and WAIS summary scores and subtest scores were not statistically significant. In other cognitive tests, the only significant correlations with UPDRS were with the AVLT immediate recall (r = 0.65, p < .02) and delayed recall scores (r = 0.64, p < .02). Since motor complications are the hallmark of this condition, we also looked at correlations with the UPDRS motor part score and other measures separately. Again, correlations with UPDRS motor parts and WAIS results remained nonsignificant. In other cognitive tests, we found significant

or 5 dots in a group and to cross out all groups with 4 dots. In general, it took 4–5 seconds longer for patients to scan a row and cross out the targets. They also tended to be more careless, leaving more targets unmarked (omissions; M = 20.21, SD = 19.79 for the patients and M = 16.36, SD = 18.81 for the control group, respectively), but this difference was not statistically significant. Commission errors (crossing out the wrong targets) were very rare in both groups. Patients were also slower in Trail Making Test A and B, but this difference was not statistically significant. Looking at the verbal memory test scores (AVLT), we found that patients had poorer results in sum of learning trials. Both groups showed a steadily rising learning curve, but control subjects were better in initial recall (trial 1). Patients also had poorer results in immediate and delayed recall; they generally remembered two words less from the learned word list than the control group. However, only the difference in immediate recall reached statistical significance. In the recognition trial, the patients were able to recognize, in general, two words less than the control group from the initially learned word list, but the overall recognition accuracy was fairly similar in both groups. The copy score of the Rey-Osterrieth Complex Figure was not significantly different, although the patients used a more fractionated and piecemeal copying strategy. This may have caused them to recall the figure more poorly in both immediate and delayed recall trials. There were no notable differences in tests of visual orientation and direction sense (the Money Road Map test and Judgment of Line Orientation). In fluency measures, the patients had significantly poorer results in animal naming, but finding new solutions in the 5-point test was not significantly different. In the Wisconsin Card Sorting Test, the mean number of categories that subjects used for sorting was not significantly different between groups. When looking at the composition of answers, the patients had a bigger percentage of perseverative responses and perseverative errors. Although they also gave fewer conceptual-level responses, this difference did not reach statistical significance. 141

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correlations with scores of the Trail Making Test B (r = −0.57, p < .04) and with AVLT test scores: the sum of learning trials (r = 0.65, p < .02), immediate recall (r = 0.75, p < .003), delayed recall (r = 0.74, p < .004), and recognition (r = 0.69, p < .01). The SE scale had no significant correlation with WAIS intelligence and subtest scores. Significant correlations were found with AVLT immediate recall (r = −0.75, p < .003) and Verbal Fluency (r = −0.68, p < .01). The HY scale had a similar association pattern, with AVLT immediate recall (r = 0.66, p < .01) and Verbal Fluency (r = 0.62, p < .02) being the only statistically significant correlations.

Selikhova et al., 2008; Yildirim et al., 2009). In contrast, Levin (2005) reported that about half of patients with MME had a’ moderate’ deficit, and, in addition, roughly a third of his sample had a’ mild’ deficit. This finding was based on comparison of the study sample with respective test reference norms, and this does not fully take into account the possible effects of demographic factors. Cognitive performance is usually influenced by demographic variables (e.g. education). When the normative data is based on a sample with a larger proportion of subjects with higher education, the test norms may underestimate the results in groups with a larger proportion of less-educated subjects. Further, it is desirable to compare the subjects with their own cultural and linguistic norms, but, unfortunately, non-English-speaking populations do not have such norms for many neuropsychological tests (Maruta et al., 2011). This can, in turn, confuse the effects seen in comparisons; therefore, a control group should be included in the analysis to account for possible demographic effects on test results. Koksal et al. (2014) compared the results of 9 patients with a demographically matched control group. They found that patients had lower abilities in short-term memory, verbal recall and non-verbal memory and also in some tests of executive skills and calculation ability. Still, in some tasks the group means differed only by a margin of less than 1 or 2 score points (Digit Span Test, WMS Visual Memory total score, MMSE Calculation). This difference is difficult to note or to consider important at the individual level. Also, they did not find significant differences in language, visuospatial functions and constructive ability, some executive tests, and thinking skills. The measures used in our study and in Koksal et al. overlap in only 5 tests, which does not allow us to make a more direct comparison between the studies. Due to the rare occurrence of this condition, study sample sizes are usually small, so group results may depend more strongly on the lower scores of only some members in a group as outliers. Therefore, the statistical difference seen in the group comparison may not amount to a real clinical relevance. We were able to include 14 subjects who were diagnosed with MME. When looking at the variability of test data, the standard deviations of patients’ test results are fairly similar to those of the control group in most measures. Visual inspection of data did not reveal notable differences in groups in terms of variance or outliers. Therefore, the results were not influenced by the discrepant results of a few individuals. An exception to this was motor performance in the Grooved Pegboard test, which was very easy for the control group to perform. Two patients were unable to perform this task with either hand, and a suggestive maximum score of 300 s was recorded as their result. When comparisons were done leaving these patients out, the profile of results or significance pattern did not change. Studies of environmental and occupational exposure to manganese have not given a conclusive picture about the effects of manganese on cognitive abilities. Some researchers have reported that demographic factors can better explain the cognitive changes (Greiffenstein and LeesHaley, 2007; Lees-Haley et al., 2006). We found that patients with MME had few significant differences in comparison with the matched control group, although the cognitive performance of patients was weaker by a small margin. Number of environmental and occupational studies have also indicated a pattern of lowered motor and cognitive levels in subjects exposed to manganese (e.g. Bowler et al., 2007a, 2007b; Klos et al., 2006; Kornblith et al., 2018). However, we cannot compare the outcome of these studies and our results directly. Different routes of manganese exposure should be considered as influencing factors; while the usual way in an occupational context is by inhalation of toxic fumes (in the case of welders or factory workers), our patients received manganese by direct intravenous injections with much higher exposure, which may result in a higher level of toxicity. It is also important to consider the possible effect of methcathinone on cognitive abilities. This study has some limitations. The group of patients was small; we were able to include only 14 subjects with MME for this study. There were several confounding factors, like HCV and HIV infection and a history of head trauma in one case, as well as concomitant consumption

4. Discussion In this study, we examined a group of patients with MME and assessed their cognitive status. So far, most of the studies of patients with MME have concentrated on neurological symptoms and physical condition. Only two studies have reported a more thorough analysis of the neuropsychological status of these patients (Koksal et al., 2014; Levin, 2005). We compared the results of 14 patients with a group of matched control subjects and found, in general, a favorable cognitive outcome. Deficits were most notable in motor skills in both dominant and nondominant hands. Lowered ability was also observed in psychomotor speed, some verbal and nonverbal memory test scores, and in some aspects of executive, verbal, and non-verbal ability. Some of these effects are partly secondary, as the tests that were used require motor responses (e.g. Rey-Osterrieth Complex Figure, WAIS Object Assembly). Due to a motor deficit, the speeded verbal responses were likewise difficult, and that can explain lower scores in Verbal Fluency. Still, this motor constraint had no effect on some other tests that require manual response (e.g. WAIS Block Design, Trail Making, 5-Point Test). When controlling for multiple comparison of the results, only three measures remained significant (WAIS Object Assembly, Grooved Pegboard, Verbal Fluency). Most of the effect sizes of the tests used were in’ moderate’ range (0.3–0.5). The effects of motor skills, psychomotor speed and verbal fluency were’ large’ (> 0.5). Most of our patients had moderate restrictions in ADL, and they needed some assistance. We did not find a clear pattern of associations between cognitive abilities and clinical status. Anecdotal evidence also supports the view that the clinical picture, course, and prognosis of this condition are highly individual. Some patients show marked motor problems, but their judgement and reasoning remain sharp; other patients may have only slight motor impairment, but their mental reactions are slow. Also, when questioned about their history of drug abuse, some patients reported active use of methcathinone for a number of years before symptoms become apparent, but, in some cases, neurological changes already appeared after some months of drug use. So far, the exact pathology of this condition has not been confirmed by histological studies. Imaging studies (Juurmaa et al., 2016; Stepens et al., 2010) have shown widespread neurological damage with manganese accumulation targeted to a number of midbrain areas (globus pallidus, substantia nigra, subthalamic nucleus, substantia innominata, putamen, caudate, dentate nucleus). Some cerebral cortical thinning is also observed, but large areas of prefrontal, parietal, and temporal cortex are spared. In addition, diffusion tensor imaging has shown widespread white matter abnormality, especially in the globus pallidus – cortical connections and areas underlying the premotor cortex (Stepens et al., 2010). We speculate that the difference between motor and cognitive change can partly be explained by this pattern of accumulation. Cognitive skills involve cortical activation of widespread neural networks, while motor skills are more dependent on certain circuits and subcortical pathways. Therefore, there might be more compensatory possibilities for cognitive skills than for motor functions. Our results are in agreement with some case reports in which only mild or minor cognitive deficits were found, mostly in tests requiring motor response (Colosimo and Guidi, 2009; Sanotsky et al., 2007; 142

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of other drugs and alcohol in some cases. None of the patients had AIDS or hepatic cirrhosis. Possible additive effects on cognitive deficits cannot be ruled out. Since our participant groups are small, some potential differences may have been undetected due to low statistical power. As this condition is rare, it is not possible to include more study subjects. Low motivation of patients to participate in a lengthy testing was also a limiting factor. All of our subjects were Russian speakers, but only a few cognitive tests are standardized and normed for a Russian population. Considering the neurological status of this condition, cognitive tests that do not require considerable motor effort and that do not have restrictive time limitations are more suitable for assessment. In future studies, it is also important to look at the behavioral effects and consequences on these patients (e.g. psychiatric changes or reactions). To summarize, our study shows limited cognitive deficits and a rather good outcome in number of cognitive domains for patients with MME. This is in contrast with pronounced motor disability observed in these patients. Clinical features are highly variable, extending from only minor changes in movement and balance to the complete inability to walk and stand freely. Compared to these physical deficits, the cognitive profile is less affected.

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