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Archives of Clinical Neuropsychology 00 (2020) 1–9

Symbol Digit Modalities Test: Greek Normative Data for the Oral and
Written Version and Discriminative Validity in Patients with Multiple
Sclerosis
Lambros Messinis1, *, Christos Bakirtzis2 , Mary Helen Kosmidis3 , Alexandra Economou4 ,
Grigorios Nasios5 , Emmanouil Anyfantis5,6 , Spiridon Konitsiotis6 , Aikaterini Ntoskou7 , Eleni Peristeri8 ,
Efthymios Dardiotis8 , Nikolaos Grigoriadis2 , Phillipos Gourzis9 , Panagiotis Papathanasopoulos10
1
Neuropsychology Section, Departments of Neurology and Psychiatry, University Hospital of Patras and University of Patras Medical School, Patras, Greece
2
B’Department of Neurology and the MS Center, AHEPA University Hospital, Central Macedonia, Thessaloniki, Greece
3
Laboratory of Cognitive Neuroscience, School of Psychology, Aristotle University of Thessaloniki, Greece
4
Department of Psychology, School of Philosophy, University of Athens, Athens, Greece
5
Department of Speech and Language Therapy, School of Health Sciences, University of Ioannina, Ioannina, Greece
6
Department of Neurology, University of Ioannina Medical School, Ioannina, Greece
7
Rehabilitation Unit for Patients with Spinal Cord Injury, “Demetrios and Vera Sfikas” Department of Medicine,
University of Patras Medical School, Patras, Greece
8
Department of Neurology, University of Thessaly Medical School, Larissa, Greece
9
Department of Psychiatry, University of Patras Medical School, Patras, Greece
10
University of Patras Medical School, Patras, Greece
*Corresponding author at: Neuropsychology Section, Departments of Neurology and Psychiatry, University Hospital of Patras and University of Patras
Medical School, Rio, Patras 26500, Greece. Tel: 0030 2613603348, Fax: +30 2611121886. E-mail address: lmessinis@upatras.gr, lmessinis3@gmail.com (L.
Messinis).
Received 26 December 2019; revised 18 February 2020; Accepted 2 April 2020

Abstract
Objectives: The purpose of this study was to generate normative data on the Symbol Digits Modalities Test (SDMT) for the
written and oral versions in the Greek adult population. We also investigated the test’s validity in discriminating the performance
of healthy adults from two groups of adults diagnosed with relapsing remitting (RRMS) and secondary progressive (SPMS)
multiple sclerosis.
Method: The sample consisted of 609 healthy men and women between the ages of 18 and 65. All participants were monolingual
native Greek adult speakers. Each healthy participant was administered either the written (n = 460) or oral (n = 149) versions
of the SDMT. Discriminant validity was examined by comparing 35 healthy participants who had completed the oral version of
the SDMT to 35 age - and education-matched RRMS and SPMS patients.
Results: Linear regression models explained between 36% and 55% of the variance in the SDMT oral and written version scores.
Age was the strongest predictor of difference in SDMT written and oral version performance, followed by education that also
accounted for a further proportion of the SDMT variance. On the contrary, gender was found not to contribute significantly to the
variance in the SDMT for either the written or the oral versions. As a result, age- and education-adjusted norms were generated.
Regarding the tests discriminative validity, we found that both MS patient groups scored significantly lower than the healthy
group.
Conclusions: This is the first study to provide comprehensive normative data for the SDMT in the adult population in Greece,
impacting the future practice of neuropsychological assessment in this country.

Keywords: Symbol digits modalities test (SDMT); Oral and written versions; Normative data; Discriminative validity; Relapsing remitting multiple sclerosis;
Secondary progressive multiple sclerosis

© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permission@oup.com.
doi:10.1093/arclin/acaa028
2 L. Messinis et al. / Archives of Clinical Neuropsychology 00 (2020); 1–9

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Introduction

Comprehensive neuropsychological assessment is essential in everyday clinical practice for the valid evaluation of cognitive
functions (Lezak, Howieson, Bigler, & Tranel, 2012). In recent years, there has been an increasing demand for standardized
and valid assessment instruments in Greece. Considering the well-documented effect of culture on differences in performance
in nearly all domains of neuropsychological functioning (Lezak et al., 2012; Strauss, Sherman, & Spreen, 2006), a number of
core neuropsychological tests have been adapted and standardized in Greece, providing normative data for the Greek adult and
child population (Kosmidis, Vlahou, Panagiotaki, & Kiosseoglou, 2004; Messinis et al., 2007; Zalonis et al., 2007; Messinis,
Malegiannaki, Christodoulou, & Papathanasopoulos, 2011; Malegiannaki et al., 2019; Nasios et al., 2016). However, the number
of valid neuropsychological instruments for both healthy populations and people with chronic diseases in Greece is limited.
The Symbol Digit Modalities Test (SDMT; Smith, 1982; Smith, 2007) was developed as a cognitive instrument sensitive to
neurological disorders. In particular, it measures information processing speed, divided attention, complex scanning and visual
tracking, and is considered a reliable tool in detecting deficits in these cognitive domains. In addition, recent research with a
computerized version of this test has suggested that working memory may in part influence the performance of the participants
(Patel, Walker Lisa, & Feinstein, 2017). It consists of nine symbols, each one associated with a number from 1 to 9. The
participant is required to match each symbol with its corresponding number within the time period of 90 s. Maximum correct
responses are 110.
The SDMT has a written and oral version. It has been suggested that both written and oral administrations should be given
whenever possible in order to permit comparisons between the two response modalities (Lezak et al., 2012). A large performance
decrement between the two response modalities is a possible indicator of dysfunction in the modality with the lower performance.
Neither order of presentation nor recency of the initial administration has been found to influence performance (Lezak et al.,
2012). Moreover, the written format of the SDMT has been purported to be an ideal screen for individuals who have disorders
of speech (Strauss et al., 2006).
Considering the influence of demographic variables on SDMT performance, time-dependent substitution tasks, such as the
SDMT, have been reported to undergo rapid nonlinear age declines after mid-life and are highly associated with educational
level (Lezak et al., 2012; Strauss et al., 2006). As such, several studies have generated normative data for the SDMT for different
ethnic populations in recent years. Normative data have been established for Danish (Vogel, Stokholm, & Jørgensen, 2013),
Australian (Kiely, Butterworth, Watson, & Wooden, 2014), Latin American (Arango-Lasprilla et al., 2015) and Dutch healthy
adults (Burggraaff, Knol, & Uitdehaag, 2017).
Information processing speed is a prerequisite cognitive function that influences the integrity of other cognitive operations,
and deficits in this domain negatively influence other cognitive abilities (Salthouse, 1996). Deficits in processing speed are
frequently evident in brain damaged patients of different etiologies, including multiple sclerosis MS (Lezak et al., 2012;
Messinis, Nasios, Kosmidis, Kambanarou, & Papathanasopoulos, 2018). The main advantage of the SDMT is that it is an
easy-to-administer and quick cognitive tool that makes it suitable for everyday clinical practice.
The SDMT is commonly administered as a cognitive screening instrument in the clinical evaluation of cognition in MS. One
of the most frequently disordered cognitive domains in MS is the reduced speed of information processing (Langdon, 2011;
Ntoskou et al., 2018). Information processing speed decline may also contribute to impairment in language abilities such as
auditory comprehension and articulation of speech that are common in MS (Friedova et al., 2019; Oreja-Guevara et al., 2019).
Currently, it is difficult to assess MS-associated cognitive impairment in routine neurological visits. Brief cognitive-screening
measures have been proposed to substitute for the more comprehensive neuropsychological test batteries, which are time
consuming and do not allow application in daily clinical practice (Bakirtzis et al., 2018). However, the lack of appropriate
normative data, from different language groups, currently limits their applicability.
A number of recent research reports propose that the SDMT is a sensitive and valid tool in detecting impairment in processing
speed in MS patients (Strober et al., 2018; Van Schependom et al., 2014). The oral version of this test is also included in the
commonly administered brief neuropsychological battery, the Brief International Cognitive Assessment for MS, that was recently
validated in Greece (Polychroniadou et al., 2016). The SDMT is also included in most batteries suitable for monitoring cognitive
function in MS, according to the American Academy of Neurology (Rae-Grant et al., 2015); therefore, alternate forms have been
developed in order to minimize practice effects in follow-up testing (Benedict et al., 2012).
In addition to the aforementioned clinical characteristics, one advantage of the SDMT is that it is strongly correlated with
magnetic resonance imaging (MRI) in MS (Rao et al., 2014). Regarding its neuroanatomical basis, the cerebral regions that
 L. Messinis et al. / Archives of Clinical Neuropsychology 00 (2020); 1–9 3

Table 1. Demographic characteristics of participants

Group Variable Value
Healthy written administration group (n = 460) Gender (men/women) 192/268

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Age (years; mean [SD]) 41.7 (16.4)
Education (years; mean [SD]) 11.4 (6.2)
Healthy oral administration group (n = 149) Gender (men/women) 53/96
Age (years; mean [SD]) 40.4 (12.5)
Education (years; mean [SD]) 14.2 (5.3)
Relapsing remitting MS (n = 151) Gender (men/women) 58/93
Age (years; mean [SD]) 39.1 (9.9)
Education level (n [SD]) 14.2 (3.5)
Disease duration (years; mean [SD]) 7.7 (4.6)
Secondary progressive MS (n = 52) Gender (men/women) 20/32
Age (years; mean [SD]) 49.5 (8.1)
Education (years; mean [SD]) 12.7 (3.2)
Disease duration (years; mean [SD]) 14.4 (6.8)
Notes: MS = multiple sclerosis; SD = standard deviation.

appear to be recruited during its administration are areas in the frontoparietal and occipital cortex (Silva et al., 2019; Silva,
Spedo, Barreira, & Leoni, 2018). This information is important since it may provide the clinician or researcher with additional
functional information regarding the neural substrates that may be affected over the course of the disease. Furthermore, ecological
validity of the SDMT has been demonstrated in MS as performance in testing strongly correlates with the vocational status of
patients (Kavaliunas et al., 2019; Strober, Chiaravalloti, Moore, & De Luca, 2014).
Due to the absence of normative data for the SDMT in Greece, in the present study, we sought to provide current normative
data for the oral and written versions for clinical and research purposes for the healthy adult Greek population. We also
investigated the test’s validity in discriminating the performance of healthy adults from two groups of adults diagnosed with
relapsing remitting (RRMS) and secondary progressive (SPMS) MS. Furthermore, we provide performance data for RRMS and
SPMS patients among differing disease duration and Expanded Disability Status Scale (EDSS) scores. The EDSS is used to
describe disease progression in patients with MS and to assess the effectiveness of therapeutic interventions in clinical trials.
It consists of an ordinal rating system ranging from 0 (normal neurological status) to 10 (death due to MS). The lower scale
values of the EDSS measure impairments based on the neurological examination, while the upper range of the scale (>EDSS
6) measures handicaps of patients with MS (Meyer-Moock, Feng, Maeurer, Dippel, & Kohlmann, 2014).

Materials and Methods

Participants

Four groups of participants took part in the study: a nonclinical (healthy) group that was administered the written version
of the SDMT (n = 460; mean age = 41.70; mean educational level = 11.40 years); a nonclinical (healthy) group that was
administered the oral version of the SDMT (n = 149; mean age = 40.40; mean educational level = 14.20 years); and two
clinical groups diagnosed with multiple sclerosis, according to the 2017 Revised McDonald Criteria (Thompson et al., 2018):
one with a relapsing remitting course (RRMS) (n = 151; mean age = 39.10; mean educational level = 13.20 years; median
[range] EDSS = 3.0 [2.0–5.0]) and a second with a secondary progressive course (SPMS) (n = 52; mean age = 49.50; mean
educational level = 12.70 years; median [range] EDSS = 5.5 [4.0–6.0]). SPMS patients were free of any relapses or MRI activity
at least 12 months prior to inclusion in the study; none of these progressive patients received disease modifying treatment, and
no activity was observed during the study duration. Both clinical groups were administered the oral version of the SDMT. All
participants were monolingual native Greek speakers whose primary language was Greek. Table 1 presents the demographic
characteristics for the nonclinical (healthy) and MS groups that completed the SDMT.

Procedure

The nonclinical groups were recruited from southwestern and northern Greece (sample of convenience) and participated in
the present study voluntarily, after providing written informed consent for their participation. Potential nonclinical participants
were approached and recruited by the experimenters with the goal of including a broad range of adult ages and education
4 L. Messinis et al. / Archives of Clinical Neuropsychology 00 (2020); 1–9

levels. They were further invited to take part in the study by their general practitioners (family doctors which in most cases
are general pathologists in Greece) in order to improve study participation and compliance. Alternatively, they were healthy
relatives of patients who were invited to take part in the study by the staff (medical doctors, psychologists) of the outpatient

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Neuropsychology Unit, Department of Neurology, University of Patras Medical School. The recruited sample is typical of the
Greek population, and participants came from both urban and rural areas.
These participants were screened, based on a clinical interview that was conducted by the researchers. Exclusion criteria
were: (1) recent diagnosis of drug or alcohol abuse or any history of major psychiatric disorders (i.e., major depression, bipolar
disorder, psychotic disorder, neurocognitive disorder or severe learning disability) based on DSM V—criteria. On this basis,
we excluded six potential participants from those initially invited to participate, (2) participants suffering from any neurological
disease (e.g., stroke, traumatic brain injury) that might affect neuropsychological performance. On this basis, we excluded only
two participants from those initially invited to participate, (3) participants suffering from any other medical condition or those
that were undergoing a pharmaceutical regimen that might affect neuropsychological performance and (4) participants that were
nonnative Greek speakers. Likewise, nonclinical participants above the age of 60 that scored below 27 on the Mini-Mental State
Examination (Fountoulakis, Tsolaki, Chantzi, & Kazis, 2000), which is used as a brief screening measure for global cognitive
deficits, were also excluded. Nonclinical participants were administered either the oral or written versions of the SDMT in a
standardized way, ensuring stabilized operating conditions.
The two MS patient groups were assessed in the Memory and Neuropsychology Unit of the Patras University Hospital
outpatient neurology clinic and the Multiple Sclerosis Center at AHEPA Hospital of Aristotle University of Thessaloniki.
Both centers followed the exact same protocol when assessing patients. The oral version of the SDMT was administered in
a standardized way, ensuring stabilized operating conditions (quiet room, fatigue factor impact, etc.) within the framework
of a short battery of neuropsychological tests at the beginning of the testing session. These included the Verbal Fluency Test
(Kosmidis et al., 2004), the Rey Auditory-Verbal Learning Test (Messinis, Tsakona, Malefaki, & Papathanasopoulos, 2007), the
Brief Visuospatial Retention Test—R (Benedict, 1997) and the Beck Depression Inventory-short form (Beck, Steer, & Brown,
2000). The dependent variable was the number of correct oral substitutions within 90 s.

Results

Statistical Analysis

We initially observed our data visually to determine whether the distributions met normality requirements. All data points that
were considered outliers or extreme outliers were excluded from analyses (scores were considered outliers if they exceeded 2
SD from the mean and extreme outliers if they exceeded 3 SD from the mean). The normality assumption of our data was further
investigated using the Kolmogorov–Smirnov test for normality. Most of our variables were normally distributed, so parametric
tests were mainly employed. We initially calculated the demographic variables for all groups. Stepwise multiple linear regression
analyses were then used to examine the potential contribution of demographic variables (age, gender and years of education) to
the performance on the SDMT. One-way analysis of variance (ANOVA) was performed with Tukey post hoc analysis to compare
groups with respect to SDMT performance. Furthermore, we calculated 95% confidence intervals (CI) on SDMT performance
among differing disease duration and EDSS scores. The level of statistical significance was set at p = .05, and analyses were
conducted using the IBM SPSS Statistics for Windows, Version 25.0 ( IBM Corp., Armonk, NY).

Contribution of Demographic Variables on the Oral and Written Versions of the SDMT

In order to examine the potential contribution of demographic variables (gender, level of education, age) to the performance
on the oral and written versions of the SDMT, we conducted linear regression analyses for each nonclinical group (see Table 2).
Results showed that age and education contributed significantly to the performance on both the SDMT-oral and SDMT-written
versions. Specifically, for the SDMT group that completed the written version, in step 1, age was placed in the equation, with
adjusted R2 = 0.36, F(1, 459) = 261.90 and p < .001. Age and education were selected in step 2, with adjusted R2 = 0.45,
F(2, 459) = 189.25 and p < .001. Age was the strongest predictor of difference in SDMT written performance, β = −0.60,
followed by education that also accounted for a further proportion of the SDMT variance, β = 0.30. The same pattern of results
was replicated for the SDMT group that completed the oral version. In step 1, age was placed in the equation, with adjusted
R2 = 0.46, F(1, 148) = 127.70 and p < .001. Age and education were placed in step 2, with adjusted R2 = 0.55, F(2, 148) = 90.19
and p < .001. Age was the strongest predictor of differences on SDMT oral performance, β = −0.68, followed by education
that also accounted for additional SDMT variance, β = 0.31. On the contrary, gender was found not to contribute significantly
to the variance in the SDMT for either the written version, β = −0.02 and p = .603, or the oral version, β = 0.77 and p = .173.
 L. Messinis et al. / Archives of Clinical Neuropsychology 00 (2020); 1–9 5

Table 2. Linear regression analyses: Contributions of age and level of education on SDMT performance in the healthy groups
Group Significant predictors Beta weights Change in adjusted R2 F change
Healthy written Step 1 Age –.60 .36 261.90∗∗∗

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administration Step 2 Age –.63
(n = 460) Education .30 .45 189.25∗∗∗
Healthy oral Step 1 Age –.68 .46 127.70∗∗∗
administration Step 2 Age –.59
(n = 149) Education .31 .55 90.19∗∗∗
Significance level: ∗ p < .05, ∗∗ p < .005, ∗∗∗ p < .001.

Table 3. Normative data stratified by age and level of education: M (SD) in the healthy written administration group
Age 18–29 (n = 131) 30–39 (n = 114) 40–49 (n = 70) 50–59 (n = 75) 60–64 (n = 25) ≥65 (n = 45) Percentile
ranking

Education 1–8 9–12 ≥12 1–8 9–12 ≥12 1–8 9–12 ≥12 1–8 9–12 ≥12 1–8 9–12 ≥12 1–8 9–12 ≥12
29.6 27.0 33.3 23.6 25.0 38.0 18.0 27.0 32.0 13.0 25.0 30.0 10.0 36.0 35.0 4.0 14.0 15.0 2nd
34.0 27.0 39.4 33.1 35.0 38.3 19.5 27.0 33.5 14.0 25.0 33.0 12.0 36.0 35.0 5.0 14.0 16.0 5th
47.0 27.0 51.0 42.3 43.0 44.0 28.0 40.0 43.5 26.0 35.0 41.8 30.0 38.3 38.5 6.3 17.0 18.3 25th
53.5 58.0 57.0 48.5 49.0 51.0 41.0 43.0 48.0 38.0 43.0 48.0 41.0 46.0 45.0 11.5 29.0 28.0 50th
61.0 64.0 65.0 54.0 55.0 58.0 47.3 60.0 55.5 44.0 46.8 51.5 43.5 48.3 48.3 27.5 39.0 39.0 75th
Mean 53.9 54.3 56.7 48.1 44.7 51.3 39.1 48.1 48.8 36.4 41.6 47.8 29.6 44.0 43.5 15.6 34.3 34.9
SD 11.2 12.8 9.9 10.0 10.2 9.6 11.4 12.7 7.9 13.2 7.8 9.1 12.0 5.4 5.7 10.9 8.2 12.4
Note: SD = standard deviation.

Table 4. Normative data stratified by age and level of education: M (SD) in the healthy oral administration group
Age 18–29 (n = 28) 30–39 (n = 57) 40–49 (n = 26) 50–59 (n = 22) ≥60 (n = 16) Percentile
ranking

Education 1–8 9–12 ≥12 1–8 9–12 ≥12 1–8 9–12 ≥12 1–8 9–12 ≥12 1–8 9–12 ≥12
45.0 47.0 51.0 46.0 52.0 58.0 36.0 42.0 44.0 – 9.0 14.0 11.0 21.0 36.0 2nd
45.0 48.0 52.0 47.0 49.0 55.9 36.0 42.0 45.0 – 12.0 17.0 12.0 21.0 36.0 5th
47.0 55.0 58.0 53.0 55.5 63.3 37.0 48.0 53.8 – 30.0 36.0 23.0 28.5 38.0 25th
58.0 63.0 66.0 54.0 65.0 71.0 52.0 58.0 61.5 – 40.0 47.5 25.0 33.5 40.0 50th
60.0 70.0 73.0 62.0 71.3 72.8 54.0 65.5 75.0 – 47.0 53.5 28.0 37.5 43.0 75th
Mean 52.5 63.3 65.8 57.7 61.8 69.7 51.7 57.4 62.7 – 37.0 47.9 25.6 31.7 39.0
SD 12.7 9.9 10.4 7.2 10.8 11.7 15.5 11.1 13.7 – 13.6 10.6 4.0 8.4 2.0
Note: SD = standard deviation.

Given the significant contribution of age and education to SDMT performance as revealed by the regression analyses for both
healthy groups, and in order to generate normative data for the Greek adult population, we grouped our written and oral form
samples into demographic categories. Graphs illustrating changes over the age range for the written administration yielded six
age groups: 18–29, 30–39, 40–49, 50–59, 60–64 and ≥65-years old. Graphs illustrating changes over the age range for the oral
administration yielded five age groups: 18–29, 30–39, 40–49, 50–59 and ≥60-years old. We also grouped our samples based on
the level of education so as to reflect school requiremets in Greece (compulsory education is 9 years): 1–9, 10–12 (high school)
and 13 years and above (higher education including technological and other university level education). Tables 3 and 4 present
means, standard deviations and percentile performance stratified by age and education level separately for the written and oral
administration versions of the SDMT.

Discriminant Validity in MS Patients

In order to determine the validity of the SDMT in discriminating MS patient groups, that is, RRMS and SPMS patients from
healthy participants, we compared 35 healthy participants who had completed the oral version of the SDMT to 35 education-
and age-matched RRMS and SPMS patients. The three groups did not differ either in age [F(2, 104) = .545, p = .581] or
education level [F(2, 104) = .141, p = .869]. A one-way ANOVA revealed a significant group effect on SDMT performance
[F(2, 104) = 16.778, p < .001]. Subsequent post hoc (Tukey) analyses revealed that the group effect stemmed from the fact that
6 L. Messinis et al. / Archives of Clinical Neuropsychology 00 (2020); 1–9

Table 5. SDMT performance in MS patient groups and healthy oral administration form participants
Group Age (years; mean [SD]) Education (years; mean [SD]) SDMT (mean [SD])
Healthy oral form (n = 35) 45.7 (7.7) 11.9 (2.6) 52.9 (17.3)

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Relapsing remitting MS (n = 35) 44.7 (3.9) 11.6 (2.1) 37.3 (14.9)
Secondary progressive MS (n = 35) 46.3 (7.3) 12.2 (3.0) 32.8 (13.2)
Notes: MS = multiple sclerosis; SDMT = Symbol Digit Modalities Test; SD = standard deviation.

Table 6. Symbol Digit Modalities Test performance among differing disease durations and EDSS scores
Group SDMT mean (SD)
Relapsing remitting MS (n = 151) Disease duration
<10 years 48.1 (15.5)
≥10 years 39.6 (15.1)
Difference (95% CI) −8.5 (−10.2 to −4.1)
EDSS = 0–3.0 51.4 (14.3)
EDSS = 3.5–10.0 38.2 (12.6)
Difference (95% CI) −13.2 (−15.9 to −5.8)
Secondary progressive MS (n = 52) Disease duration
<10 years 35.6 (11.0)
≥10 years 33.2 (12.1)
Difference (95% CI) −2.4 (−3.9 to −1.1)
EDSS ≤ 5.0 34.3 (11.6)
EDSS = 5.5–10.0 31.7 (11.3)
Difference (95% CI) −2.3 (−3.6 to −1.4)
Note: CI = confidence interval, EDSS = Expanded Disability Status Scale.

both patient groups scored significantly lower than the healthy group who completed the oral version of the SDMT (p < .001
for both comparisons). On the other hand, there was no significant difference between the two patient groups (p = .435), (see
Table 5).

Clinical Group Analyses

In order to establish whether our MS patient’s performance was influenced by disease duration and disability status (EDSS),
we split our RRMS group into two subgroups using disease duration of 10 years. This duration period was based on a study
by Amato, Ponziani, Siracusa, and Sorbi (2001) who noted that 10 years after their baseline cognitive assessment, cognitive
dysfunction was likely to emerge and progress in a sizable proportion of MS patients. Furthermore, they noted that as the disease
advances, neurological and cognitive involvement tends to converge. Moreover, Strober and colleagues (2018) utilized the same
10 year duration period when evaluating the psychometric properties of the SDMT in order to compile evidence supporting the
utilization of this measure in future clinical trials. We then compared the performance of those patients with disease duration
of less than 10 years to those of more than 10 years. Our findings indicated that RRMS patients with longer disease duration
performed on average 8.50 points lower on the oral version of the SDMT.
When conducting a similar analysis with EDSS score, using a score of 3.0 as a cut-off (based on studies that cognitive
impairment is present in patients with low disability status, that is, (EDSS) less than 3, but is less severe, see Messinis, Anyfantis,
Paschali, & Papathanasopoulos, 2009; Migliore et al., 2017), we found that RRMS patients with less than 3.0 on the EDSS
performed on average 13.2 points higher on the oral version of the SDMT compared with patients with higher levels of disability.
When we conducted the same comparisons for SPMS patients, we noted that those with longer disease duration (over 10 years)
performed on average 2.40 points lower on the oral version of the SDMT. As was expected, SPMS individuals with a higher
EDSS (over 5.5) had lower SDMT scores. On average, this difference was 2.30 points (see Table 6).

Discussion

Neuropsychologists in Greece continue to face challenges when assessing Greek-speaking individuals due to limited
availability of normative data for numerous neuropsychological measures. In the present study, we developed comprehensive
normative data for the SDMT in the Greek adult population stratified by age and level of education for both the oral and written
versions of this measure. To date, only limited normative data from a preliminary study have been generated on the SDMT in
 L. Messinis et al. / Archives of Clinical Neuropsychology 00 (2020); 1–9 7

Greece (Argirokastritou, Samanda, & Messinis, 2005). Moreover, as the SDMT is increasingly used as a screening and follow-
up tool to detect cognitive deficits in MS patients, appropriate normalization and validation in different language groups are
needed. In this respect, we evaluated the discriminative validity of the SDMT in Greek RRMS and SPMS patients.

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Although demographic variables and socioeconomic status were not found to impact test performance in healthy adults in a
relatively large community-based SDMT normative study (Sheridan et al., 2006), more recent studies (Arango-Lasprilla et al.,
2015; Burggraaff et al., 2017; Fellows & Schmitter-Edgecombe, 2019; Kiely et al., 2014; Vogel et al., 2013) have reported that
age, gender and education may influence normal SDMT performance. In the healthy samples presented here, linear regression
models explained between 36% and 55% of the variance in the SDMT oral and written version scores. Age was the strongest
influencing variable on both the oral and written versions, followed by education, which also accounted for a further proportion
of the SDMT variance. The overall pattern of performance indicated that SDMT scores increased linearly as a function of age and
education. For both healthy groups, older participants with a lower educational level performed worse than younger participants
with a higher educational level.
SDMT results from previous studies are somewhat difficult to compare directly with our data, since they are typically
presented in different age and education intervals. The data from our study, however, resemble data reported in previous studies
(see Sheridan et al., 2006; Vogel et al., 2013), especially when comparing people with more than 12 years of education. Generally
speaking, however, differences noted between normative data reports in the literature likely reflect both differences in the
sampled populations, and methodological differences in generating age- and education-based norms.
As the quality of formal education may potentially differ between countries, it is important to utilize education-adjusted
norms generated specifically for that country when administering and interpreting performance on the SDMT. To this end, age-
and education-adjusted normative data were generated for healthy adults aged 18–65 in Greece for both versions of the SDMT.
Formal education in Greece has changed over the years in Greece, and older participants have on average less years of
education than younger participants. Clinicians should consider this aspect when interpreting performance from the generated
normative data.
On the other hand, gender was not found to significantly account for the variance on the SDMT, for either the written or
oral versions. This finding is generally in line with the literature, as gender effects in previous studies have been found to
be inconsistent and even diminished when controlling for handedness (Lezak et al., 2012; Strauss et al., 2006). In light of the
present findings and the previous literature, we did not stratify participant’s performance by gender in our study when generating
normative data and calculating percentiles.
In accordance with the current literature, the SDMT is considered the measure of choice for MS trials in assessing cognitive
processing speed (Strober et al., 2018). Slowed cognitive processing has been identified as a core symptom of multiple sclerosis
over a century ago by Charcot (Charcot, 1877) and more recent reports have confirmed this finding (Langdon, 2011; Ntoskou
et al., 2018; Papathanasiou, Messinis, Georgiou, & Papathanasopoulos, 2014; Potagas et al., 2008). Furthermore, processing
speed is a basic elemental cognitive function required by and, therefore, influencing downstream processes such as learning,
memory, word retrieval, and executive function (Costa, Genova, DeLuca, & Chiaravalloti, 2017). Thus, it is of critical importance
in any neuropsychological assessment.
The present study confirmed that the SDMT adequately discriminates both RRMS and SPMS patient performance from
healthy adult scores. Our findings also suggest that SDMT performance in MS individuals appears to be more closely associated
to disease severity as measured by the EDSS than it is to disease duration. Our data further confirm the discriminative validity
of the SDMT given the expectation that individuals with MS with higher EDSS and longer disease duration would have greater
cognitive deficits and, therefore, lower scores on the SDMT. This finding supports the inclusion of a cognitive measure to fully
capture MS disability progression.
In summary, this study provides the first comprehensive reference data for the adult population in Greece for one of the most
frequently used neuropsychological measures, the SDMT, both in clinical practice and for research purposes. It also confirmed
the clinical utility of the SDMT in discriminating between healthy adult performance and individuals with MS.

Limitations

The presented normative data need to be interpreted within the context of the study’s limitations. One of the most important
limitations lies in the fact that our sample size for the oral administration was relatively small compared with the written
version, and educational level was high. Due to this limited sample for the oral administration, small cell sizes were evident
in some groups, (e.g., adults older than 60). We were also unable to generate normative data for adults aged 50–59 with less
than 8 years of education. Moreover, although many of our participants in both administered versions had less than 8 years
of education, we excluded individuals who were unable to read or write; thus, the SDMT normative data cannot generalize to
illiterate individuals. Furthermore, the healthy participants recruited in this study were a sample of convenience. Despite these
8 L. Messinis et al. / Archives of Clinical Neuropsychology 00 (2020); 1–9

limitations, the normative data presented here are representative of the Greek adult population and are directly relevant to Greek
clinical practice and research.

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Funding

This study did not receive any specific funding.

Conflict of Interest

The authors report no conflict of interest.

Research ethics

Approval was granted by the ethic committees from each institution that provided MS participants or facilitated participant
recruitment for this study.

Acknowledgements

The authors gratefully thank all participants who took part in this study and their family members for their support and
participation that lead to the realization of the present investigation.

References

Amato, M. P., Ponziani, G., Siracusa, G., & Sorbi, S. (2001). Cognitive dysfunction in early-onset multiple sclerosis: A reappraisal after 10 years. Archives of
Neurology, 58, 1602–1606.
Arango-Lasprilla, J. C., Rivera, D., Rodriguez, G., Garza, M. T., Galarza-del-Angel, J., Rodriguez, J., et al. (2015). Symbol digit modalities test: Normative
data for the Latin American Spanish speaking adult population. Neurorehabilitation, 37, 625–638.
Argirokastritou, E., Samanda, T., & Messinis, L. (2005). Preliminary normative data for the symbol digit modalities test symbol digit modalities test (SDMT)
in Greece. In Paper presented at 10th Panhellenic Congress of Psychology. Ioannina: Greece.
Bakirtzis, C., Ioannidis, P., Messinis, L., Nasios, G., Konstantinopoulou, E., Papathanasopoulos, P., et al. (2018). The rationale for monitoring cognitive function
in multiple sclerosis: Practical issues for clinicians. The Open Neurology Journal, 12, 31–40.
Beck, A. T., Steer, R. A., & Brown, G. K. (2000). BDI-fast screen for medical patients: Manual. San Antonio, TX: The Psychological Corporation.
Benedict, R. H. B. (1997). Brief visuospatial memory test–revised: Professional manual. Odessa, FL: Psychological Assessment Resources, Inc.
Benedict, R. H., Smerbeck, A., Parikh, R., Rodgers, J., Cadavid, D., & Erlanger, D. (2012). Reliability and equivalence of alternate forms for the symbol digit
modalities test: Implications for multiple sclerosis clinical trials. Multiple Sclerosis, 18, 1320–1325.
Burggraaff, J., Knol, D. L., & Uitdehaag, B. M. J. (2017). Regression-based norms for the symbol digit modalities test in the Dutch population: Improving
detection of cognitive impairment in multiple sclerosis. European Neurology, 77, 246–252.
Charcot, J. M. (1877). Lectures on the diseases of the nervous system. London: New Sydenham Society.
Costa, S. L., Genova, H. M., DeLuca, J., & Chiaravalloti, N. D. (2017). Information processing speed in multiple sclerosis: Past, present, and future. Multiple
Sclerosis, 23, 772–789.
Fellows, R. P., & Schmitter-Edgecombe, M. (2019). Symbol digit modalities test: Regression-based normative data and clinical utility. Archives of Clinical
Neuropsychology, April 25, pii: acz020. doi: 10.1093/arclin/acz020.
Friedova, L., Rusz, J., Motyl, J., Srpova, B., Vodehnalova, K., Andelova, M., et al. (2019). Slowed articulation rate is associated with information processing
speed decline in multiple sclerosis: A pilot study. Journal of Clinical Neuroscience, 65, 28–33.
Fountoulakis, K. N., Tsolaki, M., Chantzi, H., & Kazis, A. (2000). Mini mental state examination (MMSE): A validation study in Greece. American Journal of
Alzheimer’s Disease and Other Dementias, 15, 342–345.
Kavaliunas, A., Danylaite Karrenbauer, V., Gyllensten, H., Manouchehrinia, A., Glaser, A., Olsson, T., et al. (2019). Cognitive function is a major determinant
of income among multiple sclerosis patients in Sweden acting independently from physical disability. Multiple Sclerosis, 25, 104–112.
Kiely, K. M., Butterworth, P., Watson, N., & Wooden, M. (2014). The symbol digit modalities test: Normative data from a large nationally representative sample
of Australians. Archives of Clinical Neuropsychology, 29, 767–775.
Kosmidis, M. H., Vlahou, C. H., Panagiotaki, P., & Kiosseoglou, G. (2004). The verbal fluency task in the Greek population: Normative data and clustering and
switching strategies. Journal of the International Neuropsychological Society, 10, 164–172.
Langdon, D. W. (2011). Cognition in multiple sclerosis. Current Opinion in Neurology, 24, 244–249.
Lezak, M. D., Howieson, D. B., Bigler, E. D., & Tranel, D. (2012). Neuropsychological assessment (5th ed.). New York: Oxford University Press.
Malegiannaki, A., Aretouli, E., Metallidou, P., Messinis, L., Zafeiriou, D., & Kosmidis, M. H. (2019). Test of everyday attention for children (TEA-Ch): Greek
normative data and discriminative validity for children with combined type of attention deficit - hyperactivity disorder. Developmental Neuropsychology,
44, 189–202.
 L. Messinis et al. / Archives of Clinical Neuropsychology 00 (2020); 1–9 9

Messinis, L., Anyfantis, E., Paschali, A., & Papathanasopoulos, P. (2009). Cognitive deficits in relapsing remitting multiple sclerosis patients with low disability
status. In Proceedings of the 7th International Congress on the Improvement of the Quality of Life on Dementia, Parkinson’s Disease (, pp. 31–35).
Epilepsy, MS: Muscular Disorders and Neuroethics.
Messinis, L., Kosmidis, M. H., Tsakona, I., Georgiou, V., Aretouli, E., & Papathanasopoulos, P. (2007). Ruff 2 and 7 selective attention test: Normative data,

Downloaded from https://academic.oup.com/acn/advance-article-abstract/doi/10.1093/arclin/acaa028/5834363 by Uppsala Universitetsbibliotek user on 15 May 2020

discriminant validity and test-retest reliability in Greek adults. Archives of Clinical Neuropsychology, 22, 773–785.
Messinis, L., Tsakona, I., Malefaki, S., & Papathanasopoulos, P. (2007). Normative data and discriminant validity of rey’s verbal learning test for the Greek
adult population. Archives of Clinical Neuropsychology, 22, 739–752.
Messinis, L., Malegiannaki, A., Christodoulou, T., & Papathanasopoulos, P. (2011). Color trails test: Normative data and criterion validity for the Greek adult
population. Archives of Clinical Neuropsychology, 26, 322–330.
Messinis, L., Nasios, G., Mougias, A., Politis, A., Malefaki, S., Zampakis, P., et al. (2016). Age and education adjusted normative data and discriminative
validity for rey’s auditory verbal learning test in the elderly Greek population. Journal of Clinical and Experimental Neuropsychology, 38, 23–39.
Messinis, L., Nasios, G., Kosmidis, M. H., Kambanarou, M., & Papathanasopoulos, P. (2018). Neuropsychological features of multiple sclerosis: Impact and
rehabilitation: Editorial. Behavioural Neurology, 2018, Article ID 4831647, 4 pages.
Meyer-Moock, S., Feng, Y. S., Maeurer, M., Dippel, F. W., & Kohlmann, T. (2014). Systematic literature review and validity evaluation of the expanded
disability status scale (EDSS) and the multiple sclerosis functional composite in patients with multiple sclerosis. BMC neurology, 14, 58. doi:
10.1186/1471-2377-14-58.
Migliore, S., Ghazaryan, A., Simonelli, I., Pasqualetti, P., Squitieri, F., Curcio, G., et al. (2017). Cognitive impairment in relapsing-remitting multiple sclerosis
patients with very mild clinical disability. Behavioural Neurology, 7404289.
Ntoskou, A., Messinis, L., Nasios, G., Martzoukou, M., Makris, G., Panagiotopoulos, E., et al. (2018). Cognitive and language deficits in multiple sclerosis:
Comparison of relapsing remitting and secondary progressive subtypes. The Open Neurology Journal, 12, 19–30.
Oreja-Guevara, C., Ayuso Blanco, T., Brieva Ruiz, L., Hernández Pérez, M. Á., Meca-Lallana, V., & Ramió-Torrentà, L. (2019). Cognitive dysfunctions and
assessments in multiple sclerosis. Frontiers in Neurology, 10, 581. doi: 10.3389/fneur.2019.00581.
Papathanasiou, A., Messinis, L., Georgiou, L. V., & Papathanasopoulos, P. (2014). Cognitive impairment in relapsing remitting and secondary progressive
multiple sclerosis patients: Efficacy of a computerized cognitive screening battery. ISRN Neurology, 151379.
Patel, V. P., Walker Lisa, A. S., & Feinstein, A. (2017). Deconstructing the symbol digit modalities test in multiple sclerosis: The role of memory. Multiple
Sclerosis and Related Disorders, 17, 184–189.
Polychroniadou, E., Bakirtzis, C., Langdon, D., Lagoudaki, R., Kesidou, E., Theotokis, P., et al. (2016). Validation of the brief international cognitive assessment
for multiple sclerosis (BICAMS) in Greek population with multiple sclerosis. Multiple Sclerosis and Related Disorders, 9, 68–72.
Potagas, C., Giogkaraki, E., Koutsis, G., Mandellos, D., Tsirempolou, E., Sfagos, C., et al. (2008). Cognitive impairment in different MS subtypes and clinically
isolated syndromes. Journal of the Neurological Sciences, 267, 100–106.
Rae-Grant, A., Bennett, A., Sanders, A. E., Phipps, M., Cheng, E., & Bever, C. (2015). Multiple sclerosis quality measures: Executive summary. Neurology,
85, 1904–1908.
Rao, S. M., Martin, A. L., Huelin, R., Wissinger, E., Khankhel, Z., Kim, E., et al. (2014). Correlations between MRI and information processing speed in MS:
A meta-analysis. Multiple Sclerosis International, 975803. doi: 10.1155/2014/975803.
Salthouse, T. A. (1996). The processing-speed theory of adult age differences in cognition. Psychological Review, 103, 403–428.
https://doi.org/10.1037/0033-295X.103.3.403.
Sheridan, L. K., Fitzgerald, H. E., Adams, K. M., Nigg, J. T., Martel, M. M., Puttler, L. I., et al. (2006). Normative symbol digit modalities test performance in
a community-based sample. Archives of Clinical Neuropsychology, 21, 23–28.
Silva, P. H. R., Spedo, C. T., Baldassarini, C. R., Benini, C. D., Ferreira, D. A., Barreira, A. A., et al. (2019). Brain functional and effective connectivity
underlying the information processing speed assessed by the symbol digit modalities test. NeuroImage, 184, 761–770.
Silva, P. H. R., Spedo, C. T., Barreira, A. A., & Leoni, R. F. (2018). Multiple Sclerosis Outcome Assessments Consortium (MSOAC). Symbol digit modalities test
adaptation for magnetic resonance imaging environment: A systematic review and meta-analysis. Multiple Sclerosis and Related Disorders, 20, 136–143.
Strober, L., Chiaravalloti, N., Moore, N., & De Luca, J. (2014). Unemployment in multiple sclerosis (MS): Utility of the MS functional composite and cognitive
testing. Multiple Sclerosis, 20, 112–115.
Strober, L., DeLuca, J., Benedict, R. H. B., Jacobs, A., Cohen, J. A., Chiaravalloti, N., et al. (2018). Symbol digit modalities test: A valid clinical trial endpoint
for measuring cognition in multiple sclerosis. Mult Scler., 18:1352458518808204. doi: 10.1177/1352458518808204.
Smith, A. (1982). Symbol digits modalities test. Los Angeles: Western Psychological Services.
Smith, A. (2007). Symbol digits modalities test: Manual. Los Angeles: Western Psychological Services.
Strauss, E., Sherman, E. M. S., & Spreen, O. (2006). A compendium of neuropsychological tests: Administration, norms, and commentary (3rd ed.). New York:
Oxford University Press.
Thompson, A. J., Banwell, B. L., Barkhoff, F., Caroll, W. M., Coetzee, T., Comi, G., et al. (2018). Diagnosis of multiple sclerosis: 2017 revisions of the
McDonald criteria. The Lancet Neurology, 17, 163–173.
Van Schependom, J., D’hooghe, M. B., Cleynhens, K., D’hooge, M., Haelewyck, M. C., De Keyser, J., et al. (2014). The symbol digit modalities test as sentinel
test for cognitive impairment in multiple sclerosis. European Journal of Neurology, 21, 1–8.
Vogel, A., Stokholm, J., & Jørgensen, K. (2013). Performances on symbol digit modalities test, color trails test, and modified stroop test in a healthy, elderly
Danish sample. Aging, Neuropsychology, and Cognition, 20, 370–382.
Zalonis, I., Kararizou, E., Triantafyllou, N. I., Kapaki, E., Papageorgiou, S., Sgouropoulos, P., et al. (2007). A normative study of the trail making test A and B
in Greek adults. Clinical Neuropsychologist, 22, 842–850.