J Neurol (1991) 238:351-354

Journal of

Neurology
© Springer-Verlag 1991

Korsakoff's syndrome as the initial presentation of multiple sclerosis
Alain Vighetto, Nadine Charles, Martin Salzmann, Christian Confavreux, and Gilbert Aimard
Clinique de Neurologie, H6pital Neurologique P. Wertheimer, 59, Boulevard Pinel, F-69003 Lyon, France
Received September 19, 1990 / Received in revised form January 4, 1991 / Accepted January 18, 1991

Summary. A 37-year-old m a n p r e s e n t e d with a n acute
a m n e s t i c s y n d r o m e of K o r s a k o f f ' s type a n d a n u p p e r
b r a i n - s t e m o c u l o m o t o r s y n d r o m e . A f t e r a m o d e r a t e imp r o v e m e n t with steroid t h e r a p y , he d e v e l o p e d progressive b e h a v i o u r a l changes d u e to a f r o n t a l l o b e s y n d r o m e ,
in a d d i t i o n to m o t o r a n d visual i m p a i r m e n t . M e m o r y
p e r f o r m a n c e was i n v e s t i g a t e d o n several occasions during an l l - y e a r follow-up. D i a g n o s i s of l a b o r a t o r y - s u p p o r t e d definite m u l t i p l e sclerosis was e s t a b l i s h e d a n d
m a g n e t i c r e s o n a n c e i m a g i n g showed d i s s e m i n a t e d white
m a t t e r lesions, especially in b o t h m e d i a l t e m p o r a l lobes.
N o o t h e r cause t h a n m u l t i p l e sclerosis was f o u n d for the
amnestic s y n d r o m e . A m o n g the rare cases of Korsakoff's
s y n d r o m e in the course of m u l t i p l e sclerosis, this is to
o u r k n o w l e d g e the first case in which a m e m o r y deficit
was the initial m a n i f e s t a t i o n of the disease.

Key words: K o r s a k o f f ' s s y n d r o m e - M u l t i p l e sclerosis

Introduction
It is well k n o w n f r o m the initial d e s c r i p t i o n b y C h a r c o t
[9] that " w e a k e n i n g of m e m o r y " (affaiblissement de la
m6moire) f r e q u e n t l y occurs in the later stages of disabling m u l t i p l e sclerosis (MS). H o w e v e r , m e m o r y loss is
u s u a l l y o n l y o n e c o m p o n e n t of a g e n e r a l i z e d i n t e l l e c t u a l
deficit with p e r s o n a l i t y changes. S o m e r e p o r t s have
s h o w n that cognitive i m p a i r m e n t , d i s p r o p o r t i o n a t e l y severe c o m p a r e d with the m o t o r disability, p r e s e n t i n g as
d e m e n t i a or frontal lobe s y n d r o m e , m a y occur soon after
o n s e t of the disease [4, 12, 16, 18, 34]. W e p r e s e n t a n app a r e n t l y u n i q u e case of definite MS in which a severe
a m n e s t i c s y n d r o m e of K o r s a k o f f ' s type was the initial
m a n i f e s t a t i o n of the illness.

Case report
A 37-year-old right-handed man, an advertising manager, was referred in November 1978 with a 10-day history of memory loss.

Offprint requests to: A. Vighetto

Three months previously, he had been hospitalized in the department because of a depressive episode. At that time, neurological
examination, including memory, was unremarkable. Initial evaluation showed an attentive and cooperative patient with severe amnestic syndrome. Memory for recent events was poor. He could
not recall his first admission to the hospital or his recent visit to the
doctor. Details of his daily life as well as current political events
were not remembered and he made repeated queries about his
state of health. It took him several days to learn the topography of
the department. He could repeat seven verbal items, but he was
unable to recall a single one of five words after a 5-min delay. By
contrast, he was oriented to place, to month and year and he only
failed to give the date. Remote memory was fair, as he could give
correctly his age, personal address, autobiographical landmarks,
as well as the name of the current French president and major
historical facts. He had no confabulation. He was aware of his
trouble, but mildly unconcerned and dysphoric. Oral language,
reading, writing, praxis, visuospatial perception, calculation and
visual fields were normal. Otherwise, neurological examination
was remarkable for bilateral tendon hyper-reflexia with Babinski's
sign, restriction of upward gaze with vertical nystagmus, paralysis
of convergence, and bilateral internuclear ophthalmoplegia. The
patient was afebrile, continent and fully ambulatory. Initial and
subsequent CT and EEG were normal. CSF contained 2 leucocytes/
mm3, 0.44 g/l protein, and the IgG/protein ratio was 9.8%, without
oligoclonal bands. Extensive screening for infectious agents, including virus cultures and antibody titres in serum and CSF was
negative, in particular for herpes virus. Visual evoked responses
with alternating checker-boards showed pathologically delayed responses for both eyes. Despite this unusual presentation, a diagnosis
of probable MS was suspected and steroid therapy was started.
Neuropsychological testing demonstrated poor learning performances for both verbal and visual materials. Rey's auditory verbal
learning test showed a flat curve; he recalled 6, 7, 7 and 6 of the 15
words along the four successive trials, and only 6 words in recognition. Lhermitte and Signoret's spatial location learning test [20]
was similarly affected. While normal subjects memorize the spatial
location of the 9 pictures in a maximum of four trials, with no more
than 6 errors (false localization) during these trials, the patient
could learn only 3 pictures at the fourth trial with a total of 26 errors. These tests were performed again 3 weeks later, after steroid
treatment. Improvement was noted only for the spatial location
test, as he placed 8 pictures after four trials and made only 10 errors. Rey's figure was easily copied, but poorly recalled after 5 min
(score: 11; normal range: 28-36). In February 1979, the Rey's verbal learning curve remained flat (5, 6, 5, and 6 of the 15 words), although the performance was better in recognition (9/15). Visual
learning was higher, as in Lhermitte and Signoret's test, he could
now place the 9 pictures at the first trial. His performance dropped
to 5/9 pictures in a recall condition, in which he had to describe the
picture corresponding to each location (normal lower limit: 7), but

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Table 1. Modified Signoret and Wbiteley's [20] memory scale performance ~
Verbal memory

Short-term logical memory
Serial learning
Paired-associate learning
Logical memory/delayed recall
Serial memory/delayed recall
Recognition memory

Visual memory

October 1984

March 1989

Controls (SO) b

October 1984

Controls (SD) b

3
5
4
1
5

4.5
6.5
1
3
1

9.9 (1.2)
9.1 (1.2)
11.5 ( . 8 )
10.1 (1.2)
9.4 (1.3)

7
3.5
8
5
6

9.4 (1.4)
8.9 (1.5)
11.4 ( . 9 )
9 (1.3)
8.8 (1.8)

-

8

11

-

-

(.9)

" Both verbal and visual memory were tested in October 1984, but only verbal memory in March 1989
b Age and education-adjusted controls (n = 55)

remained normal in the recognition test, as he could show the location of the 9 pictures presented individually to him. In March 1979,
as memory continued to improve, the patient was able to recall and
comment on current political events. This improvement contrasted,
however, with passive behaviour. He stayed dysphoric and unconcerned; for the next few years he remained at his parents' home,
where he had the assistance of his parents.
The patient was not again examined by us until October 1984.
During the time elapsed, new neurological signs and symptoms
had progressively appeared. He then presented with gait disturbances and micturition difficulties, and he used a stick to walk. He
had a moderately severe static and kinetic cerebellar syndrome,
and mild tetraparesis with left Babinski's sign, in addition to upward gaze paralysis, bilateral internuclear ophthalmoplegia and
the vertical nystagmus previously noted. He also had left trigeminal neuralgia. Corrected visual acuity was 10/10 for the right eye
and 5/10 for the left eye. Furthermore, the patient exhibited severe
neurobehavioural abnormalities. He was apathetic, unconcerned
and euphoric. He denied any problem but the facial pain. He could
not see any reason that prevented him from resuming his work.
However, he had remained in his parents' charge for the last 5
years. He used to spend hours lying in bed, reading magazines or
watching TV. He obeyed commands but he had no initiative. His
affect was puerile and he occasionally made inappropriate jokes.
He was cooperative but poorly motivated. His verbal span was 6
forward and 4 backward. He could give quickly six names of flowers. Mental control was altered as he failed to perform serial subtractions. He was oriented to time and place, he could name the
current French president, the prime minister, comment on recent
political and sporting events, and give an accurate description of
his life. However, there was a striking discrepancy between these
good factual memory performances and the poor scores he obtained in more formal testing. The modified Signoret and
Whiteley's battery [29] confirmed that both verbal and visual
memory were altered, the latter to a lesser extent (Table 1). Other
cognitive functions were much less affected. IQ determined with
Wechler's scale was 110 (verbal IQ = 123, performance IQ = 92).
Elaborate language, including proverb interpretation and judgement on nonsense stories was spared, as well as calculation, and
constructions. There was no apraxia, no grasp reflex, and the patient could perform fairly well the Luria's sequences. At this time,
a second course of high-dose steroid therapy was initiated, without
any beneficial effect, and azathioprine treatment (100 mg/day) was
started.
The patient was readmitted in March 1989. His neurobehavioural status remained remarkably unchanged, while his motor disability had become worse, causing him to use a wheelchair because
of paraplegia and cerebellar ataxia. His IQ stayed in the high normal range (110; verbal IQ = 111, performance IQ = 108). However, the deterioration index was abnormal (26%). Verbal memory was tested with the same battery as in 1984 (Table 1). Learning
scores remained low, with very poor performance in delayed recall
contrasting with subnormal results in recognition. Magnetic resonance imaging (MRI) showed diffuse hyperintense punctuate sig-

Fig. 1. MRI showing demyelinating lesions in the brain stem and in
both medial temporal lobes (spin echo: 60/1800)
nals on T2-weighted sequences mainly in periventricular areas and
in the white matter of both medial temporal lobes (Fig. 1).

Discussion
Several recent psychometric studies have revealed that
subclinical or mild cognitive deficits can often be demons t r a t e d in M S [8, 14, 19, 26]. T h i s m a y o c c u r e v e n in pat i e n t s w i t h m i l d p h y s i c a l d i s a b i l i t y [14, 24, 33], a n d at t h e
first a t t a c k o f t h e d i s e a s e [7, 23]. T a s k s p r o b i n g m e m o r y
a r e m o s t f r e q u e n t l y a l t e r e d in t h e s e n e u r o p s y c h o l o g i c a l
s t u d i e s a n d t h e n a t u r e o f t h e d e f i c i t has b e e n e x t e n s i v e l y
a n a l y s e d . T h e r e is a m p l e d o c u m e n t a t i o n o f s h o r t - t e r m
memory deficit affecting recall and recognition for both
v e r b a l a n d n o n - v e r b a l m a t e r i a l [2, 14, 26, 30]. V a r i o u s
p a t t e r n s h a v e e m e r g e d , l a r g e l y d e p e n d i n g o n t h e tests
used and the population under study. Thus, poor perform a n c e s h a v e b e e n r e l a t e d to i m p a i r m e n t in r e t r i e v a l
s t r a t e g i e s [2, 6], r e d u c e d l e a r n i n g [33], a c c e l e r a t e d forg e t t i n g [33], s e m a n t i c e n c o d i n g d e f i c i t [8], o r s l o w i n g o f
i n f o r m a t i o n p r o c e s s i n g [1, 2, 21]. R e m o t e m e m o r y c o u l d
also b e a l t e r e d [2, 3]. In c o n t r a s t to this w e a l t h o f d a t a ,
the pure amnestic syndrome of Korsakoff's type seems
e x t r e m e l y r a r e in M S . W e a r e a w a r e o f o n l y five p r i o r rep o r t s [10, 13, 17, 31, 32]. U l e [32] d e s c r i b e d a y o u n g m a n
w h o d e v e l o p e d an a c u t e a m n e s t i c s y n d r o m e a n d d e l u sions. A s p o s t m o r t e m e x a m i n a t i o n r e v e a l e d d e m y e l i n a t -

353
ing loci in both A m m o n ' s horns and fornices, it was considered that this was a case of acute MS. Kamalian et al.
[17] described a case of malignant encephalopathy with
hypothalamic cachexia and poorly described anterograde
amnesia, initially intermittent then p e r m a n e n t . Neuropathological examination led to a diagnosis of MS. Demyelinating plaques were disseminated, with noticeable
involvement of the left lateral hypothalamic area, mamillary body and both fornices. As amnesia had occurred
when the patient was cachectic, one cannot rule out an
additional role for a nutritional factor. Gherardi et al.
[13] presented a case of rapidly progressive m e m o r y loss
with internuclear ophthalmoplegia occurring a few months
after a resolving optic neuritis. Pathological study of the
brain showed co-existing l y m p h o m a and demyelinating
lesions. The most likely lesion to explain the m e m o r y deficit was an inflammatory necrosis of the fornix with secondary atrophy of the mamillary bodies. H o w e v e r , lymp h o m a extended to the splenium of the corpus callosum,
the amygdala, the hypothalamus and the left internal
temporal lobe. Regarding the nature of these demyelinating changes, the authors favoured the diagnosis of
MS, but could not rule out the possibility of l y m p h o m a t ous lesions mimicking MS. The case of Trillet et al. [31]
is one of definite MS in which an acute amnestic synd r o m e followed a status epilepticus. The authors discussed on clinical grounds the possible role of anoxic changes
in hippocampal regions previously damaged by demyelinating lesions. The case of Feinstein and R o n [10] also
had definite MS, but Korsakoff's syndrome occurred in
the course of severe and chronic alcohol intoxication.
A r g u m e n t s that MS was a causative or even a contributing factor to the m e m o r y disturbances in this context are
obviously slim in the absence of pathological correlations. Thus, all the above cases are opened to criticism.
A m o n g the three patho-anatomical cases, two had a very
atypical course for MS and one had associated cerebral
lesions, while in the two clinical cases, another factor
was present to contribute to amnesia. In comparison,
our case appears to be unique for at least three reasons.
First, this is a laboratory-supported definite case of MS
according to the criteria of Poser et al. [25]; although
no patho-anatomical confirmation is available, an 11year follow-up in addition to clinical, biological, electrophysiological and imaging data can reasonably exclude
any other cause for the m e m o r y deficit. Second, a subacute anterograde amnestic syndrome occurred as the
initial s y m p t o m of the illness, and was only associated
with brain-stem oculomotor disturbances. This initial
syndrome pointed to a diencephalo-mesencephalic lesion, and was much m o r e suggestive of a thalamo-mesencephahc paramedian infarction, a Korsakoff-Wernicke's
encephalopathy or a viral encephalitis than of MS; despite this, the correct diagnosis was suspected quite early
after rapid exclusion of other possibilities. Third, neuropsychological investigations were p e r f o r m e d longitudinally. They have d o c u m e n t e d two separate evolutive
trends over time. On the one hand, anterograde amnesia
was initially severe and persisted chronically over years
after a m o d e r a t e i m p r o v e m e n t which took place in a few
weeks. On the other hand, despite i m p r o v e m e n t of am-

nesia, self-generated behaviour worsened because of
progressive development of a typical frontal lobe syndrome. The amnesia pattern was complex and changed
with time, probably as a consequence of the crossing
evolution of the two syndromes. Thus, the initial stage
was characterized by p o o r learning abilities for all types
of tests, and later stages by a deficit more m a r k e d for recall with relatively preserved recognition, suggesting a
prevailing deficit on retrieval strategies. Thus, our case
seems to have combined a very unusual subacute Korsakoff's syndrome from a partly remitting first attack
with a much m o r e c o m m o n frontal lobe syndrome, a
m a r k e r of the severity of the disease in its progressive
form [2, 3].
The anatomical basis of cognitive dysfunction in MS
remains controversial. Cortical atrophy and ventricular
size [27] as well as the degree of white m a t t e r involvement detected by M R I [7, 11, 28] have been correlated
with the severity of intellectual deficit, but some authors
did not find such a correlation [15, 22]. A recent study
with M R I showed that anterograde m e m o r y deficit
could be linked to demyelination of both medial temporal lobes [5]. In our case, precise correlation was not
available as M R I was p e r f o r m e d 10 years after the onset
of Korsakoff's syndrome; however, the most severe
changes were present bilaterally in the medial temporal
lobes, suggesting that demyelination of both hippocampal regions and surrounding white matter areas might
represent a likely basis for the persistent amnestic syndrome.

Acknowledgement. We thank Mme O.Hibert who performed
some of the neuropsychological tests.
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