Chronic Progressive Multiple Sclerosis
Relationship Between Cerebral Ventricular Size
and Neuropsychological Impairment
Stephen M. Rao, PhD; Sander Glatt, MD; Thomas A. Hammeke, PhD; Michael P.
B. O. Khatri, MBBS; Ann Marie Rhodes, MA; Susan Pollard, MA
\s=b\ Forty-seven patients with chronic
progressive multiple sclerosis were exam-
ined to assess the possible relationship
between cerebral atrophy (by computed
tomography [CT]) and performance on
neuropsychological tests of memory and
verbal intelligence. Nineteen patients
were found to have mildly dilated ventri-
cles and another nine patients had moder-
ate to severe ventricular enlargement.
Performance on memory and intelligence
testing was related to the degree of ven-
triculomegaly. Three linear CT measure-
ments were also recorded. Using this
method, the width of the third ventricle
proved to be the best indicator of intellec-
tual and memory dysfunction. Measures
of cognition and ventricular size did not
correlate with length of illness or overall
disability as rated by the Kurtzke Disabili-
ty Status Score.
(Arch Neurol 1985;42:678-682)
Computed tomographie (CT) studies
have shown cerebral atrophie
changes to in anywhere from
occur
20% to 57% of patients with multiple
sclerosis (MS)1'7 (Table 1). Several
studies have suggested that these
radiologie changes are associated with
dementia,1·7 although none have
Accepted for publication July 3, 1984.
From the Department of Neurology, Medical
College of Wisconsin, Milwaukee.
Read in part before the annual meeting of the
International Neuropsychological Society, Hous-
ton, Feb 3, 1984.
Reprint requests to Section of Neuropsycholo-
gy, Medical College of Wisconsin, 9001 Water-
town Plank Rd, Milwaukee, WI 53226 (Dr Rao).
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McQuillen, MD;
reported objective data to support this sis established an average of 7.4 years
clinical observation. Establishing prior to testing. The mean Kurtzke Dis¬
such a relationship with objective ability Status Score (DSS),16 a ten-point
measures is essential in this disease, rating scale of gross motor function, was
6.5 (range, 3 to 9).
since morphological changes have
been shown frequently not to corre¬
Neuropsychological Measures
late with clinical signs and symp¬
toms.8·9 Several recent neuropsycho¬ The neuropsychological test battery con¬
logical studies have suggested that a sisted of measures of verbal intelligence
substantial proportion of patients and memory. Neuropsychological testing
with MS exhibit disturbance of higher was administered by experienced examin¬
ers (A.M.R. and S.P.), who had no prior
cognitive functions, particularly in knowledge of the patients' clinical courses
the areas of memory10·11 and conceptu¬ or the results of their CT scans.
al reasoning.1213 The purpose of the Verbal intelligence was assessed with
present study was to determine three subtests from the Wechsler Adult
whether changes in brain structure, Intelligence Scale-revised version (WAIS-
as reflected in CT measures of atro¬ R)": comprehension, similarities, and
phy, are associated with a correspond¬ vocabulary. All individually reported sub-
ing degree of cognitive dysfunction in test scores were age corrected. These
scores were combined with the digit span
patients with MS with a chronic pro¬ subtest from the Wechsler Memory Scale
gressive course.
PATIENTS AND METHODS
Forty-seven patients with clinically defi¬
nite MS, as determined by the criteria
established by Schumacher et al,14 were
examined prior to undergoing plasmaphe¬
Table 1.—Percent of Patients
With MS With CT Atrophie Changes
resis and immunosuppressive drug thera¬ in Previously Reported Series*
py.15 The diagnosis was established by mul¬
tiple neurological examinations, evoked With
potentials, neuro-ophthalmological exami¬ Atrophy,
Study %
nations, and other supportive testing,
including CSF studies. Chronic progressive Hershey et al1 66 20
MS was defined as a continuous worsening Radue and
of signs and symptoms for at least six Kendall2 49 35
Reisner and
months preceding acceptance into the Maida3 43 37
study. The sample included 32 women and Jacobs and
15 men; mean age was 39.7 years (range, 21 Kinkel4 34 38
to 68 years); and average length of formal Cala et al5 100 44
education was 13.5 years (range, 10 to 18 Gyldensted6 110 46
years). Patients in this sample experienced De Weerd7 23 57
Total 425 39
their first symptoms of MS an average of
11.0 years (range, one to 36 years) prior to *ln order of increasing incidence. MS indicates
participation in the study, with the diagno- multiple sclerosis; CT, computed tomography.
 (WMS) (see following) to compute a pro¬
rated Verbal IQ. The performance subtests Table 2.—Demographic and Illness Characteristics of Three Groups of
of this intelligence test, which minimally Patients With MS With Varying Degrees of Ventricular Size"
require intact sensory (ie, visual) and fine
motor functions, were not administered Ventricular Size
because of their inappropriateness for this
Moderate-
patient population. Normal Mild Severe
The memory battery consisted of the 19
WMS18, a standard clinical assessment pro¬ Sex, M/F 7/12 2/7
cedure, and two measures of verbal (Free
Verbal Recall Test [FVRT]) and spatial Age, yr 43.6

(7/24 Spatial Recall Test [SRT]) learning Education, yr 13.6 13.5 13.3
and memory. These measures have been Years since onset of
shown previously to be reliable indicators symptoms 11.3 11.8
of memory dysfunction in patients with Years since diagnosis 7.6 9.6
MS," and are described in the following: Kurtzke Disability
WMS.—This scale consists of seven sub- Status Score 6.5
tests, yielding asummary score (Memory *MS indicates multiple sclerosis.
Quotient) corrected for age and standard¬
ized to have a mean of 100. The Visual
Reproduction subtest was scored liberally
for those patients with MS having marked Table 3. —
Mean Scores of Intellectual and
ataxia. Memory Tests for the Three MS Groups'
FVRT.— Multiple lists of 12 nouns each
were constructed from the norms of Paivio Ventricular Size Group Comparisons,
et al." The lists contained words with ten
letters or less in length and with the Moderate-
Normal Mild Severe 1 1 2
Kucera-Francis20 frequency of usage count v3
Variablet (Group 1) (Group 2) (Group 3) v2 v3
greater than one. The lists were equated WAIS-R
for word frequency and ease of free recall, Verbal IQ 101.7 95.1 90.4
as determined from the norms of Christian
(prorated)
Vocabulary 10.0 8.9
et al.21
Comprehension 9.5 <.05
During administration, the subject is 8.6
read one of the lists (list A) with a 2-s Similarities 10.f 8.8
pause between words. A period of free WMS
recall ensues, followed by four more read¬ Memory Quotient 107.3
ings of the same word list, each followed by Information 5.6
a recall period. A second list of 12 different Orientation 4.8
words (list B) is then read, followed by a Mental Control 5.2
period of free recall. The subject is then Digit Span 11.3
asked to recall words from list A. Thirty Logical Memory 6.8 05 <.05
minutes later the patient is asked to recall 9.9 8.8 <.05 <.05
Visual Reproduction
words from list A (delayed condition).
Associate Learning 14.5 10.0
Three alternate forms of this test were
FVRT
used in this study in equal proportions for
List A (5 trials) total recall
each group. No substantial differences (max 60) 38.1 28.0 •C.05
were observed between test forms; conse¬
List (max 12) <.05
quently, data were collapsed across test List A recall (max 12) 6.3 <.05
forms.
SRT.—The 7/24 test of Barbizet and List A delayed (max 12) 6.2 <05
Cany22 was modified to yield measures 7/24 SRT
comparable to the FVRT. In this test, Design A (5 trials) total
recall (max 35) 25.5 <.05
seven poker chips are randomly placed on a 4.3
6X4 checkerboard. Following a 10-s expo¬ Design (max 7)
sure, the subject is asked to reproduce the Design A recall (max 7) 5.6 4.6 4.6
original seven-chip pattern with nine chips Design A delayed (max 7) 5.4 5.2 4.1
and an empty board. Learning trials are *MS indicates multiple sclerosis; and max, maximum.
repeated four additional times with the tWAIS-R indicates Wechlsler Adult Intelligence Scale-Revised; WMS, Wechsler Memory Scale; FVRT,
same pattern (design A). One trial with a Free Verbal Recall Test; and SRT, Spatial Recall Test.
new pattern (design B) then ensues, fol¬ ¿Based on Tukey a posteriori contrast test.26
lowed by a free recall of design A. A
delayed recall of design A occurs after 30
minutes. This test of spatial learning was CT Analysis patient's age and made adjustments in his
chosen to obviate complications of inter¬ assignments based on this variable. A sim¬
pretation in patients with MS with motor Computed tomographie scans were per¬ ilar rating was also derived for sulcal
and/or visual acuity disturbances, since formed in the axial projection parallel to enlargement, although this measurement
the display is large (27.9 X 20.3 cm) and the orbital meatal line. An experienced CT proved to be unreliable and therefore is not
placement of the chips does not require rater (S.G.), who had no prior knowledge of reported.
fine motor coordination. For those patients the patients' clinical course or results of Linear measurements were recorded in
with severe ataxia, the chips were placed cognitive testing, recorded both subjective accordance with the procedures described
on the board by the examiner as directed ratings and linear measurements of cere¬ by Huckman et al.23-24 These measurements
by the verbal report of the patient. Three bral atrophy. For the subjective ratings, included the following: (1) the length of the
alternate forms of this test were used. Like the sample was divided into three groups distance between the most lateral portion
the FVRT, no differences were observed depending on whether the patients had no, of each of the frontal horns of the lateral
between test forms, and the data were mild, or moderate to severe ventricular ventricles ("bifrontal" span); (2) the width
subsequently collapsed. dilatation. The rater was provided with the of the lateral ventricles in the region of the

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Verbal
Normal (N=19)
-Mild (N 19)
-Moderate-Severe
_L
Trials
Learning curves for free verbal recall test ("verbal") and 7/24 spatial recall test ("spatial") for
three subgroups of patients with multiple sclerosis having normal ventricular size, mild dilatation,
and moderate to severe ventricular enlargement.
caudate nuclei, that being the width of the
two lateral ventricles just anterior to the
third ventricle ("bicaudate"); and (3) the
maximum width of the third ventricle
("third").
All measurements were recorded in mil¬
limeters from illuminated roentgeno-
graphic transparencies. A ventriculocran-
ial ratio was computed by dividing each
measure by its internal transverse cranial
diameter recorded at the same level.
RESULTS
CT Ratings
Nineteen patients (40% ) were rated
as having normal ventricular size for
their age, 19 (40%) were judged to
have mild atrophy, and the remaining
nine (20%) had moderate to severe
ventricular enlargement. Table 2
presents information regarding sex
distribution and mean age, education,
duration of illness, and illness severi¬
ty (DSS) for the three subgroups. A
one-way analysis of variance was per¬
formed to assess mean group differ¬
ences. None of these analyses
approached statistical significance
(P > .10).
Table 3 summarizes results of cog¬
nitive testing for the three subgroups.
One-way analyses of variance25 were
computed to compare the three sub¬
groups on each of the intelligence and
memory variables. Because the sub¬
jective atrophy ratings did not corre¬
late with age (r < .03), it was not
necessary to covary this variable.
Eleven of the 20 variables yielded
significant F ratios (P < .05). On each
of these 11 variables, a Tukey a A recall conditions, respectively) and
posteriori test was performed to
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Spatial
-
= The analysis of neuropsychological
(N=9)
L -L _L
delineate which subgroups differed
from each other (Table 3). The major¬
ity of significant group differences
(P < .05) were observed between the
two extreme groups (ie, patients with¬
out atrophy those with moderate to
severe atrophy). On two measures (Vi¬
sual Reproduction from the WMS and
recall of list from the FVRT), signif¬
icant differences (P < .05) were
observed between the mild atrophy
and moderate to severe atrophy
groups. Only one measure
Memory from the WMS) demon¬
strated a significant difference
(P < .05) between the group with nor¬
mal ventricles and the group with
mild ventricular enlargement.
Of the three WAIS-R subtests, only
Comprehension, a measure of verbal
abstraction and judgment, was re¬
lated to the degree of cerebral atro¬
phy. On the WMS, significant
(P < .05) differences were observed
between the two extreme groups on
the overall Memory Quotient. These
group differences were more apparent
on the three memory subtests (Logical
Memory, Visual Reproduction, and
Associate Learning) than on mea¬
sures of orientation and attention (eg,
Mental Control). On the experimental
memory measures (FVRT and SRT),
ventricular enlargement was associat¬
ed with poorer performance on the
verbal than spatial task, particularly
on variables sensitive to proactive and
retroactive interference effects (mea¬
sured by responses to the recall and
to delayed memory.
Learning curves derived from the
7
FVRT ("verbal") and SRT ("spatial")
tests are presented in the Figure.
Two-way repeated-measures analyses
of variance25 were performed to assess
possible differences in rates of acqui¬
sition between the groups. For both
tasks, the group main effect was sig¬
nificant (P < .05). However, the
groups X trials interactions for both
the verbal and spatial tasks were not
significant (P > .20). It was concluded
that while the three groups differed in
the amount of information acquired,
the acquisition rates for each group
were similar.
data has centered thus far on group
mean comparisons. A more clinically
relevant method of analysis would be
to assess the overall accuracy of clas¬
sification when patients are dichoto¬
mized on the basis of presence or
absence of CT atrophy and of cogni¬
tive dysfunction. To accomplish this
analysis, a stepwise discriminant
function analysis26 was performed
using a limited number of highly dis¬
criminating cognitive variables, as
determined from the statistical proce¬
dure. Correct classification was
achieved in 35 (74.5%) of 47 patients
using three cognitive measures: Com¬
prehension (WAIS-R), delayed recall
from the FVRT, and the recall con¬
dition from the SRT. Of the 12
patients who were misclassified, sev¬
en patients with enlarged ventricles
(three with moderate to severe atro¬
(Logical phy) performed normally on cognitive
measures, while five patients with
impairment on cognitive measures
had normal ventricles.
CT Linear Measurements
The linear measurements yielded
mean scores of 0.32 (SD 0.05) for the
=
bifrontal span, 0.16 (SD 0.04) for the
=
bicaudate, and 0.05 (SD 0.03) for the
=
third. Partial correlations were used
to relate linear measurements with
cognitive variables, since age signifi¬
cantly correlated with the bifrontal
index (r 33, =
.01) and marginally
=
correlated with the third index
(r =
.22, =
.07).
Table 4 summarizes intercorrela-
tions between the three linear mea¬
surements and the intellectual and
memory variables. The third ventricle
measure significantly correlated
(P < .05) most often with both intel¬
lectual and memory measures. The
negative correlations indicate that as
ventricular size increases, perfor¬
mance on cognitive measures declines.
Correlations between linear CT mea¬
sures and illness variables (ie, length
 of illness, Kurtzke DSS) were not sig¬
nificant (P > .20).
COMMENT
The findings strongly suggest that
cognitive dysfunction in chronic pro¬
gressive MS is associated with brain
atrophy, at least as reflected in mea¬
sures of CT ventricular size. With the
exception of isolated case reports, this
study appears to be the first major
attempt in patients with MS to relate
psychometric measures of cognitive
dysfunction with morphological
changes in brain structure.
The subjective global ratings of
atrophy demonstrated a better rela¬
tionship to cognitive variables than
the linear measurements, an observa¬
tion that has also been noted in the
literature on senile dementia of the
Alzheimer's type.27 In the present
study, the linear measurements
appeared to underestimate the degree
of atrophy, presumably accounting for
the significant, but relatively modest
correlations (ie, r < .40) with cogni¬
tive measures.
Of the linear measurements, the
width of the third ventricle proved to
be the best indicator of cognitive dys¬
function. We postulate two explana¬
tions for this observation. The first is
based on the technical limitations in
deriving linear measurements from
CT. Because the third ventricle is slit¬
like when viewed in the horizontal
sections of the CT scanner, increases
in width may more accurately reflect
changes in ventricular volume. On the
other hand, measuring the lateral
ventricles is more difficult because of
their irregular anatomy when viewed
in horizontal section. A second expla¬
nation would propose that the third
ventricle is a better indicator of cogni¬
tive dysfunction since it more closely
reflects the periventricular pathologic
changes in MS.28
Previous studies have demonstrated
that cognitive deficit in MS appears to
be confined to recent memory and
conceptual reasoning functions,
with only minimal involvement of lin¬
and visuo-perceptual pro¬
guistic 10i2'29
cesses. Consistent with these pre¬
vious studies, we found stronger clini-
coanatomic correlations for the mem¬
ory than verbal intellectual measures,
particularly as reflected in measures
of vocabulary usage. The observed
relationship between atrophy and the
Comprehension subtest of the WAIS-
R may be more related to deficits with
abstraction and social judgment than
with linguistic processes per se. We"·'2
have speculated that periventricular
MS plaques disrupt white matter
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Table 4.—Partial Correlations Between Linear Computed Tomography and
Neuropsychological Test Measures Controlling for Effects of Age
Variable'
WAIS-R
Verbal IQ
(prorated)
Vocabulary
Comprehension
Similarities
WMS
Memory Quotient
Information
Orientation
Mental Control
Digit Span
Logical Memory
Visual Reproduction
Associate Learning
FVRT
List A (total recall)
List
List A recall
List A delayed
7/24 SRT
Design A (total recall)
Design
Design A recall
Design A delayed
*
WAIS-R indicates Wechsler Adult
Verbal Recall test; and SRT, Spatial
tP<.05.
$P<.025.
§P<.01.
fiber tracts interconnecting prefron-
tal-limbic structures, resulting pri¬
marily in memory and conconceptual
reasoning deficits. The correlations
found in this study may suggest that
such lesions, reflected indirectly by
the degree of ventriculomegaly, may
produce this specific pattern of cogni¬
tive decline. Alternatively, the clini-
coanatomic correlation may simply
reflect the severity of diffuse cerebral
involvement.
In comparing the results of the ver¬
bal and visual-spatial experimental
memory measures, a stronger rela¬
tionship between atrophy and memo¬
ry disturbance was observed on the
FVRT. At first glance, this might
suggest a greater impairment in lin¬
guistic memory as a result of greater
left hemisphere involvement. This is
highly unlikely, however, since post¬
mortem studies have shown that cere¬
bral plaques are evenly distributed in
both hemispheres.28 Alternatively,
this finding may be due to differences
in task difficulty between the two
measures. In comparing the total
recall for the five learning trials, the
patients without atrophy (group 1)
achieved 63.5% accuracy with the
FVRT, but retrieved 87.1% of the SRT
items (Table 3). Thus, a ceiling effect
may have reduced the discriminative
'Third"
"
"Bifrontal'' "Bicaudate
-.27t
-.26t
-.33$
.32$ .37§
25t -.29t
26t .29$ .32$
.41§
-.29t -35§
.26$ .34$
.28$
-.30* .34$
.32$
.26$
-.29t .32$
-.37§
-.28$
Intelligence Scale-Revised; WMS, Wechsler Memory scale; FVRT, Free
Recall test.
power of the SRT.
The stepwise discriminant function
analysis demonstrated that 35 of 47
patients (75%) with and without CT
atrophy could be accurately classified
using a composite of three cognitive
variables. While this classification
accuracy is statistically significant,
the relatively high number of false-
positive and negative results pre¬
cludes reliable use of the CT scan as a
predictor of neuropsychological dys¬
function.
Cerebral atrophie changes were
noted in 28 of 47 patients (60% ), 19
(40% ) with mild and nine (20% ) with
moderate to severe ventriculomegaly.
These figures appear to be somewhat
higher than those reported in previ¬
ous studies (Table 1). This is likely the
result of limiting our sample to
patients with chronic progressive dis¬
ease. Thus, our sample may be more
severely impaired by the illness than
the general population of patients
with MS.
The lack of relationship between
measures of CT ventricular size and of
illness characteristics (ie, length and
severity) was somewhat surprising.
Unlike previous CT studies,15 we did
not find a relationship between length
of illness and degree of cerebral atro¬
phy. This may be the result of re-
 stricting the range of patients to those
with chronic progressive disease.
Alternatively, it is also possible that
atrophy may not occur invariably as
part of the natural course of MS;
instead, certain patients may be pre¬
disposed to cerebral demyelination.
The finding that the Kurtzke DSS, a
global rating of disease severity as
defined by the patient's mobility, was
not related to degree of cognitive dys¬
function was not surprising, since we
have noted this in previous reports."·12
1. Hershey LA, Gado MH, Trotter JL: Comput-
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of multiple sclerosis. Ann Neurol 1979;5:32-39.
2. Radue EW, Kendall BE: Iodide and xenon
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multiple sclerosis (MS). Neuroradiology 1978;
15:153-158.
3. Reisner T, Maida E: Computerized tomogra-
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4. Jacobs L, Kinkel WR: Computerized axial
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5. Cala LA, Mastaglia FL, Black JL: Comput-
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Downloaded From: http://archneur.jamanetwork.com/ by a Oakland University User on 06/07/2015
It would appear that this scale is also
unrelated to degree of ventriculomeg¬
aly.
In this study of patients with chron¬
ic progressive disease, a relatively
small percentage of patients (36%)
demonstrated direct evidence of dis¬
ease (ie, plaques) on CT scan. The CT
scan, however, has been shown to
underestimate the number and size of
plaques in the brain.30 Magnetic reso¬
nance imaging shows promise of more
effectively identifying white matter
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