Motor deficits associated with mild, chronic hyponatremia: a factor analytic study.

Abstract

Chronic hyponatremia (CHN) has traditionally been considered asymptomatic. If symptoms are observed, they are often mistakenly attributed to the underlying disorder. However, in recent studies neuropsychological deficits have been associated with CHN. The authors sought to determine the association between CHN and motor deficits. They used previously collected data, and 41 subjects with hyponatremia were included. An exploratory factor analysis with principal component analysis (PCA) was performed (eigenvalues >1.0). Factor scores were generated for each subject based on the resultant PCA factor structure. Finally, partial correlations were computed to measure the degree of association between baseline serum sodium concentration [Na+] and individual neuropsychological factor scores with the effect of age removed. All significance tests were performed using 2-tailed comparisons with alpha level of p ≤ .05. A 3-factor model emerged accounting for 70.17% of the total variance, including 1 factor that loaded primarily with motor speed and reaction time. A significant correlation was observed between this motor factor and serum [Na+] (r = -.477, p = .002). These findings add to previous observations suggesting that CHN is associated with subtle yet harmful motor deficits.

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Mot or Def i ci t s Associ at ed W i t h Mi l d, Chroni c
Hyponat rem i a: A Fact or Anal yt i c St udy
Al exander G. Geboy a , Dawn M. Fi l m yer a b & Ri char d C. Josi assen a c
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b Wal den Uni ver si t y , Mi nneapol i s, Mi nnesot a
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To ci t e t hi s art i cl e: Al exander G. Geboy , Dawn M. Fi l m yer & Ri char d C. Josi assen ( 2012) : Mot or Def i ci t s Associ at ed W i t h Mi l d,
Chr oni c Hyponat r em i a: A Fact or Anal yt i c St udy , Jour nal of Mot or Behavi or , DOI : 10. 1080/00222895. 2012. 688895
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Journal of Motor Behavior, Vol. 44, No. 4, 2012
Copyright C ?Taylor & Francis Group, LLC
RESEARCH ARTICLE
Motor Deficits Associated With Mild, Chronic Hyponatremia:
A Factor Analytic Study
Alexander G. Geboy1, Dawn M. Filmyer1,2, Richard C. Josiassen1,3
1Translational Neuroscience, LLC, Conshohocken, Pennsylvania.2Walden University, Minneapolis, Minnesota.3Department
of Psychiatry, Drexel University College of Medicine, Philadelphia, Pennsylvania.
ABSTRACT. Chronic hyponatremia (CHN) has traditionally been
considered asymptomatic. If symptoms are observed, they are often
mistakenly attributed to the underlying disorder. However, in re-
cent studies neuropsychological deficits have been associated with
CHN. The authors sought to determine the association between
CHN and motor deficits. They used previously collected data, and
41subjectswithhyponatremiawereincluded.Anexploratoryfactor
analysis with principal component analysis (PCA) was performed
(eigenvalues >1.0). Factor scores were generated for each subject
based on the resultant PCA factor structure. Finally, partial correla-
tions were computed to measure the degree of association between
baseline serum sodium concentration [Na+] and individual neu-
ropsychological factor scores with the effect of age removed. All
significance tests were performed using 2-tailed comparisons with
alpha level of p ≤ .05. A 3-factor model emerged accounting for
70.17%ofthetotalvariance,including1factorthatloadedprimarily
with motor speed and reaction time. A significant correlation was
observed between this motor factor and serum [Na+] (r = –.477,
p = .002). These findings add to previous observations suggesting
that CHN is associated with subtle yet harmful motor deficits.
Keywords: chronic hyponatremia, motor deficits, volume regula-
tion, cerebral edema
S
ficult to detect clinically, as they are often subtle and at-
tributed to the underlying disease (Decaux, 2006). The range
ofsymptomsdependschieflyontherateanddegreeofserum
[Na+] decline. Acute hyponatremia (AHN), which occurs in
24–48 hr, induces a life-threatening condition. Water dif-
fuses across the semipermeable cellular membrane into the
intracellularfluidcompartmentcausingbrainedema.Though
most cells can adjust to such edema, brain cells are partic-
ularly vulnerable to edema as the skull limits swelling to
approximately 7–8%. Beyond this limit, a number of severe
neurologicalsymptomsoccurincludingbrainstemherniation
(Schrier, 2010).
In contrast, stable chronic hyponatremia (CHN), which
develops over 48 hr or more, has been considered asymp-
tomatic when using current clinical criteria. In most cases,
symptoms of CHN appear mild and often go unnoticed by
both the patient and the physician. Water restriction is of-
ten the prescribed treatment, but if it fails to normalize
serum [Na+], clinicians are prone to overlook mild CHN
(particularly when serum [Na+] is > 125 mEq/L; Decaux,
2006).
However, a recent study by Renneboog, Musch,
Vandemergel, Manto, and Decaux (2006) reported that
patients with supposedly asymptomatic CHN presented
ymptoms related to hyponatremia (HN; HN – serum
sodium concentration [Na+] < 136 mEq/L) can be dif-
with gait disturbance and falls at approximately four times
the rate seen in controls (21% vs. 5%). Bun, Serby, and
Friedman (2011) reported similar findings among psychotic
patients with CHN. These findings have been replicated by
others (Josiassen et al., in press; Verbalis et al., 2010).
Interestingly, while Renneboog et al. (2006) reported at-
tentional impairments in their population, the attentional
findingswereprimarilybasedoncomplexreactiontimetasks
(e.g., digit span, go–no go, visual vigilance). Though within
the motor realm, these tasks interweave motor and psy-
chomotor components and cannot be unambiguously identi-
fied or interpreted without further analysis. Only Josiassen
et al. (2012) reported deficits in “pure” motor functioning
(simple reaction time) to be associated with CHN. However,
due to the amount of significant associations between serum
[Na+] and individual neuropsychological raw scores pro-
duced from their analyses (7 of 18 correlation coefficients
achieved statistical significance), the authors did not isolate
“pure” motor deficits from psychomotor or other cognitive
deficits.Instead,theauthorsstatedthatmotoranomalieswere
in part associated with reduced serum [Na+].
Thusthepurposeofthepresentstudywastoexpandonthe
work of Josiassen et al. (2012) using factor analytic proce-
durestodisentangletheputativeorthogonalfactorspresentin
the previously reported neuropsychological data. It was an-
ticipated that a more “pure” motor function factor would be
identified.Wehypothesizedthatthefunctionalconsequences
of CHN would not be associated with a global deficit com-
mon across all neuropsychological factors, but rather corre-
lated with “pure” motor deficits.
Method
Subjects and Procedure
Over a decade ago, 44 hyponatremic patients (31 men and
13women)tookpartinanefficacyandsafetystudyoftheex-
perimental compound VPA-984 (lixivaptan) for treating HN.
The original study was approved by the Institutional Review
Board at each recruitment site and conducted in accordance
withgenerallyacceptedstandardsfortheprotectionofpatient
safety and welfare. Written informed consent was obtained
from each subject prior to initiating any study procedures.
The neuropsychological battery was administered to all sub-
jects at baseline (Day 1 after serum [Na+] was assessed and
Correspondence address: Alexander G. Geboy, 180 Barren
Hill Road, Conshohocken, PA 19428, USA. e-mail: alexgeboy@
gmail.com
255
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A. G. Geboy, D. M. Filmyer, & R. C. Josiassen
TABLE 1. Baseline Demographics and Clinical
Characteristics (N = 41)
Variable
M SDn
%
Age (years)
Ethnic origin
African American
Asian
Caucasian
Other
Gender
Male
Female
Primary diagnosis
Cirrhosis
SIADH
CHF
Combination
Child-Pugh score
0
05
07
08
09
10
11
12
50.279.95
2
2
4.9
4.9
87.6
2.4
36
1
29
12
70.7
29.3
3175.6
12.2
9.8
2.4
5
4
1
9
1
2
3
6
8
6
6
22.0
2.4
4.9
7.3
14.6
19.5
14.6
14.6
Note. SIADH = syndrome of inappropriate antidiuretic hormone;
CHF = chronic heart failure.
priortoanymedicationadministration).Thebatteryincluded
a variety of motor, psychomotor, cognitive, and intelligence
testsandwasadministeredbyatrainedpsychometristateach
site. The entire battery took approximately 2.5 hr to admin-
ister (for a full description of the neuropsychological battery,
see Josiassen et al. 2012).
Ultimately, 41 of the original 44 subjects were included in
the present analysis of baseline data (see Table 1 for subject
demographics and clinical characteristics). All subjects had
HN associated with a primary medical diagnosis of either
cirrhosis (n = 31), syndrome of inappropriate antidiuretic
hormone secretion (n = 5), chronic heart failure (n = 4), or
a combination of the previous disorders (n = 1). All subjects
wereinpatientsforthedurationofthestudy.Groupmeanage
was 50.27 years (SD = 9.95 years) and mean serum [Na+]
at baseline was 125.05 mEq/L (SD = 4.78 mEq/L).
Statistical Analysis
For the present study, we conducted a series of statistical
procedures using SPSS (version 17.0). First, we screened
each variable for missing data or outliers. This resulted in
the removal of three subjects from the data set: one was
an outlier and two were missing a considerable amount of
test data. Next, we performed an exploratory factor analysis
with principal component analysis (PCA; eigenvalues > 1.0)
using the following variables: Peabody Picture Vocabulary
Test (PPVT), Trail Making Test (TMT; A and B), digit sym-
bol (DS), block design (BD), digit span (total; DSt), Benton
Line Test (BLT), simple reaction time (SRT), complex reac-
tion time (CRT), and finger tapping (FT; dominant hand).
Table 2 displays the resulting correlation matrix. Factor
scores were generated for each subject based on the resultant
factor structure. Finally, we computed partial correlations to
measure the degree of association between baseline serum
[Na+] and individual neuropsychological factor scores with
the effect of age and Child-Pugh scores removed. All sig-
nificance tests were performed using two-tailed comparisons
with alpha level of p ≤ .05.
Results
Factor Analysis and Partial Correlations
The PCA produced a three-component solution account-
ing for 70.17% of the total variance. Both the Kaiser-Meyer-
Olkin measure of sampling adequacy (0.74, greater than the
TABLE 2. Correlation Matrix
Variable123456789 10
1. Finger dom
2. Simple RT
3. Complex RT
4. Trails A
5. Trails B
6. Block design
7. Digit span (total)
8. Benton line
9. Digit symbol
10. PPVT
—
−.396
−.092
−.424
−.381
.386
.087
.256
.175
.193
—
−.251
.358
.558
−.505
−.321
−.357
−.382
−.198
—
.045
−.171
.350
.264
.490
.117
.121
—
.729
−.475
−.519
−.316
−.633
−.324
—
−.640
−.475
−.379
−.689
−.328
—
.632
.503
.694
.507
—
.389
.482
.437
—
.237
.353
—
.389 —
Note. RT = reaction time; PPVT = Peabody Picture Vocabulary Test.
256 Journal of Motor Behavior
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Motor Deficits and Hyponatremia
TABLE 3. Rotated Component Matrix and
Correlations
ComponentFactor 1 Factor 2 Factor 3
Neuropsychological tests
Finger tapping (dominant)
Simple reaction time
Complex reaction time
TMT-A
TMT-B
Block design
Digit span (total)
Benton line
Digit symbol
PPVT
% Variance explained
.062
−.242
.064
−.714
−.678
.701
.767
.261
.833
.632
45.60
−.876
.665
.075
.472
.530
−.342
.010
−.296
−.211
.001
14.04
−.038
−.354
.895
.140
−.109
.404
.299
.721
.005
.201
10.55
Partial correlation coefficients
Correlation
Significant (two-tailed)
−.114
.482
−.477
.002
−.231
.151
Note. TMT = Trail Making Test; PPVT = Peabody Picture Vocab-
ulary Test.
recommended value of 0.6) and Bartlett’s test of spheric-
ity (p < .001) indicated the data were suitable for factor
analysis.
Weexaminedwhetherthefactoranalysisdistinguishedbe-
tween motor and psychomotor domains, and if so, whether
baseline serum [Na+] would then be correlated in isola-
tion with motor deficits. Table 3 summarizes the total vari-
ance of each factor. Factor items that loaded at >.4 were
interpreted as evidence that the variance of that particu-
lar item was represented in the factor. Factor 1 comprised
six items accounting for 45.6% of the variance. It was a
heterogeneous group of cognitive tasks, including execu-
tive (TMT A and B, DSt), attention–intelligence (DS and
PPVT), and visuospatial (BD) functioning. Notably, the
PPVT, a test of pure intelligence, loads primarily in this
factor (.632), and is nearly absent in Factor 2 (.001) and
Factor 3 (.201).
Factor 2 was comprised of four items accounting for
14.04% of the variance. FT (loading of –.876) and SRT
(loading of .665) are “pure” motor speed tasks that require
minimal cognitive input. Additionally, TMT A and B loaded
onthisfactor(.472and.530,respectively).Itappearsthatthe
factor analytic procedure successfully partitioned the inter-
woven motor and cognitive aspects of the TMT into separate
orthogonal factors.
Factor 3 comprised three items accounting for 10.55% of
the variance. This last factor included psychomotor (CRT)
and visuospatial (BLT and BD) items. CRT assesses psy-
chomotor ability and is a sensitive measure of aspects in-
volving both motor planning and execution.
Table 3 summarizes the results of the partial correlations
wecalculatedbetweeneachfactorandbaselineserum[Na+],
controlled for age and Child-Pugh score. Only Factor 2,
which contained primarily motor speed and reaction time
tests, was statistically significant (r = –.477, p = .002).
Discussion
The purpose of this factor analysis was to further inves-
tigate the relationship between HN and neuropsychological
impairmentinagroupofpatientswithCHNofdiverseetiolo-
gies. Given the global nature of hyponatremic encephalopa-
thy, a global functional deficit would appear a logical
corollary. However, to the contrary, results from this sample
indicated reductions in serum [Na+] were significantly cor-
related with localized deficits in “pure” motor functioning.
In the factor analysis, “pure” motor impairment was sig-
nificantly correlated with serum [Na+], after removing the
effects of age and Child-Pugh scores (the significance of the
Child-Pugh is discussed subsequently). Though other items
in Factors 1 and 3 test motor ability (e.g., CRT), they are
predominantly assessments of cognitive functioning, and re-
quire specific skills to plan and execute a task. Only the FT
(dominant hand) and SRT tasks test—independently of other
abilities—“pure” motor ability (i.e., the FT task is a measure
ofself-directedmotorspeedandrecordstheamountoffinger
taps per minute, not directed by computer-generated tones,
or fixed intertone intervals; the SRT task records the speed
of reaction by pressing a button in response to a computer-
generated stimulus). As previously stated, though motor and
psychomotor impairment was mentioned in Josiassen et al.
(2012), it was unclear what specific variables were the pri-
mary contributors to the association with serum [Na+]. To
our knowledge, this is the first study to address specific
impairment distinguishing between motor and psychomotor
deficits.
Factor Scores
The main applications of a factor analytic technique are
to reduce the number of variables and to detect a structure
within the relationship between variables. Looking at Factor
2 (Table 3), it is clear that motor function, FT (–.876) and
SRT (.665), is the primary contributing domain in this factor,
and furthermore significantly correlates with serum [Na+]
(r = –.477, p = .002). Though FT has a strong negative load-
ing whereas SRT has a strong positive loading, the direction-
ality of any factor is mathematically arbitrary (R. Gorsuch,
personalcommunication,February23,2012),andretainsthe
internalvalidityofthefactorstructure.Theobserved internal
contrast function effect identified by contrasting signs in FT
and SRT reflects the nature of each test, where more finger
taps produces a larger number (–.876), while the shorter RT
latency produces a smaller number (.665).
Given the influence of motor functioning on Factor 2, it is
not surprising that TMT A and B loaded as well. Both tests
requireadegreeofmotorprecision,thoughtheyareprimarily
monitoring attention and task switching abilities. It is inter-
esting that TMT B loaded higher in Factor 2, as it requires a
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A. G. Geboy, D. M. Filmyer, & R. C. Josiassen
higher degree of cognitive flexibility to differentiate consec-
utively between number and letter. One explanation is this
highlightsasubtlepracticeeffect,asTMTAalwaysprecedes
TMT B in a standard testing battery. Again, although the di-
rectionality of the sign changes for both TMT tests among
Factors 1, 2, and 3, this is mathematically arbitrary and does
not devalue the internal structure. Some computer programs
leave the directionality of a sign to chance, and some reverse
the factor if the sum of loadings is negative (so that most
loadings are positive; R. Gorsuch, personal communication,
February 23, 2012).
Physiological Implications
Though the mechanisms are still unclear, these results
along with the findings of others are beginning to convinc-
ingly indicate that CHN is associated with motor deficits.
In CHN, the brain is able to achieve nearly complete cell
volumeregulation,recoveringfrommostneurologicalsymp-
tomsattributabletocerebraledemaandassociatedwithAHN
(Verbalis, 2010). However, the physiological implications of
brain cell reduction in CHN, namely the large decrease in
brain organic osmolytes, have several potentially important
functional and clinical implications related to motor deficits.
As solute losses are sustained over long periods in CHN, the
brain does not achieve homeostasis, but rather enters into an
allostatic state, attaining at most a dynamic stability.
In this chronic, allostatic state, brain solute losses are sus-
tained over long periods (Verbalis & Gullans, 1991). Of par-
ticular importance, the ongoing loss of brain glutamate (up
to 30%) particular to CHN (Verbalis & Gullans) suggests the
possibility of decreased synaptic release of excitatory neu-
rotransmitters (Verbalis, 2010). This could have significant
negative effects on neuronal synaptic transmission (Verbalis;
Verbalis & Gullans). It can lead to a lower electrochemi-
cal gradient of sodium and a weaker sodium current during
depolarization (i.e., the reversal of the resting potential in
excitable cell membranes when stimulated), and could sig-
nificantly affect nerve conduction velocity (Ar´ anyi, Kov´ acs,
Szirmai, & Vastagh, 2004). Diminished velocity would have
observable effects on long motor neurons that are rich in
intracellular glutamate. Therefore, in terms of “pure” motor
functioning(theabilityofapersontocompleteanFTorSRT
task in contrast to a TMT task), if there is in fact nerve con-
duction slowing, it could account for the motor impairment
observed in patients with CHN.
Thiscorrelationbetween“pure”motorimpairmentandre-
ducedserum[Na+]isintriguinginlightoftherelationshipto
nerve conduction slowing. Though diminished velocity itself
cannotdiscriminatebetweenmotorandpsychomotortasks,it
maybethecasethattheconsequences ofCHNarespecificto
“pure” motor activity. When a cognitive demand is added to
a motor task (i.e., differentiating between right and left index
fingers in a multiple-stimulus, complex reaction time task), a
disruption of ability would be expected. However, the ques-
tion is what part of the task is affected? As the factor scores
suggest (Table 3), it is not the cognitive but rather the motor
component that is altered by CHN. The loadings of TMT A
and B in Factor 2 are additionally supportive of this point,
as they indicate both the successful partitioning into their
cognitive and motor constituents, and further argue for the
selectiveconsequencesofCHNon“pure”motorfunctioning.
These exploratory findings are not without limitations.
First, the sample was small and data were missing for some
participants.Thismighthavelimitedthestabilityoftheresul-
tant PCA structure (Guadagnoli & Velicer, 1988). Moreover,
the small sample limited statistical power and generally in-
creased the risk of statistical error. Second, the selected tests
did not cover the full range of neuropsychological function-
ing. These findings cannot be generalized to abilities such as
executive functioning and nonverbal memory. Finally, it was
indicated in the original study that participants were con-
siderably ill and comprised mostly of those with advanced
liver cirrhosis. This makes our significant results difficult to
generalize and limits our ability to attribute causality to an
isolated disease. It is unclear to what degree other medical
complications or medications affected performance on the
neuropsychological tests, if at all.
The primary patient comorbidity in this population was
liver cirrhosis (see Table 1 for scores). To better understand
the impact of advanced liver cirrhosis on motor function-
ing in this group, we computed a partial correlation between
baseline serum [Na+] and the three factors produced by the
factor analysis with the effect of the Child-Pugh scores re-
moved. Briefly, the Child-Pugh is a measurement tool used
internationally to assess the prognosis of chronic liver dis-
ease, particularly cirrhosis (Pugh, Murray-Lyon, Dawson,
Pietroni, & Williams, 1973). Scores are given to determine
thediseasestate.Ascoreof5–6isconsideredGradeA(well-
compensateddisease),7–9isconsideredGradeB(significant
functional compromise), and 10–15 is considered Grade C
(decompensated disease; Pugh et al.). Because the majority
of our sample (n = 31) had a primary diagnosis of cirrho-
sis, it was important to examine whether severity of cirrhosis
was a contributor to the association between reduced serum
[Na+] and Factor 2 in this sample. It was determined that
with the effect of the Child-Pugh score removed, the associa-
tion between serum [Na+] and Factor 2 was still statistically
significant (r = –.316, p = .047). Controlling for age and
Child-Pugh score, the correlation between serum [Na+] and
Factor 2 was statistically significant (r = –.477, p = .002).
Thoughthesedatadonotruleoutanassociationbetweencir-
rhosis and motor deficits, they do imply that the association
between CHN and motor deficits is much more robust.
Despite these limitations, the significant correlation be-
tween CHN and motor functioning is adjacent to the lit-
erature cited above. Our finding offers yet another new and
confirmatoryreportofthesymptomaticnatureofandcompli-
cations associated with CHN. Furthermore, this result main-
tains the appeal by both Decaux (2006) and Renneboog et al.
(2006) that clinicians must attend to this condition, as it is
responsible for increased morbidity and mortality. Actively
258 Journal of Motor Behavior
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Motor Deficits and Hyponatremia
treating the condition could substantially improve patients’
quality of life (Josiassen et al., in press). This result should
be confirmed by other groups, and with other chronically
hyponatremic populations (e.g., schizophrenia). Further re-
searchshouldexplore“pure”motorandreactiontimedeficits
within the framework of brain volume regulation during hy-
poosmolality in human populations.
ACKNOWLEDGMENTS
The authors wish to express their appreciation to Dr. Cesare Or-
landi and Dr. Amber Salzman for providing access to the data. The
authors would also like to thank Dr. Richard Gorsuch for providing
guidance in statistical analysis.
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Submitted January 3, 2012
Revised April 10, 2012
Accepted April 23, 2012
2012, Vol. 44, No. 4 259
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