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Bilateral and limited amygdalohippocampal lesions causing a pure amnesic syndrome.

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Bilateral and Lrmted Amygdalohppocampal
Lesions Causing a Pure Amnesic Syndrome
C. Duyckaerts, MD,' C. Derouesne, MD,t J. L. Signoret, MD,t F. Gray, MD," R. Escourolle, MD,'
and P. Castaigne, MDt
A pure amnesic syndrome of 21 months' duration occurred in a 36-year-old man following a transient confusional state.
T h e patient died of Hodgkin's disease. At postmortem examination, bilateral and symmetrical neuronal loss, without
inflammatory changes, was restricted to the hippocampus and amygdaloid bodies.
Duyckaerts C, Derouesne C, Signoret JL, Gray F, Escourolle R, Castaigne P: Bilateral and limited
amygdalohippocampal lesions causing a pure amnesic syndrome. Ann Neurol 18:314-319, 1985
A pure amnesic syndrome of 2 1 months' duration was
observed in a :36-year-old man who died of Hodgkin's
disease. At postmortem examination, severe neuronal
loss was found that was restricted to the hippocampus
and the amygdaloid bodies. The dentate and parahippocampal gyri were spared on both sides. The cause of
these changes remains unknown. The role of hippocampal involvement in amnesia is generally accepted
[lo, 241; the importance of amygdaloid lesions is still
unclear.
Case Report
A 36-year-old white man, who was a missionary living in
Senegal, was admitted on September 18, 1971, to the Clinique des Maladies du Systeme Nerveux at the Salp@triere
Hospital because of a confusional state. He had been moderately hypertensive and had had headaches for 6 months.
Twenty-six days prior to admission he had had a surgical
exploration of the left maxillary sinus because of suspected
osteitis. Local anesthesia and a diazepam injection were administered. No osteitis was found and no incidents were
reported during the surgical procedure. In the evening of the
same day he was found walking on the street and talking
incoherently. He was brought to a neurosurgical unit in Paris
where right carotid and vertebral angiograms, pneumoencephalogram, and gamma scan were normal.
O n admission the patient was found to be emaciated; his
temperature was 38"C, and his blood pressure was 170l100
mm Hg. He was disoriented and confused. Deep tendon
reflexes were normal and equal. Plantar responses were
flexor. Electroencephalogram (EEG) showed diffuse delta
waves. Cerebrospinal fluid was clear and contained 30 lymphocytes/mm3, 92 d d l of protein, 1.3 mmole/L of glucose;
the gamma globulin ratio was 16% of total protein. Blood
From the tClinique des Maladies du Syst5rne Nerveux, Service du
professeur Castaigne, Hdpital de la Salpetrisre, 47 Bld de l'Hdpital,
and *Labratoire de Neuropathologie Charles Foix, Hdpital de la
Salpetriere, 47 Bld de I'Hdpital, 75013 Paris Cedex 13, France.
314
cell count showed 3,900,000 erythr~cyteslmm~,
16,000
leukocytes/mm3 (7 1% neutrophils, 26% lymphocytes, 3%
monocytes). Sedimentation rate was 8 5 mm at one hour.
Serum iron was 3.5 pmoVL, saturation 10%. Results of
routine laboratory tests (sodium, potassium, chloride, glucose, proteins, calcium, alkaline phosphatase, glutamic oxaloacetic transaminase, urea) were all within normal limits.
N o abnormality was noted in the bone marrow differential
cell count. Searches for T ypanosoma, Plasmodium, syphilis,
and typhoid fever produced no positive findings. Hepatitis B
virus surface antigen was absent.
Serum immunoelectrophoresis showed an increase of
alphal and alpha2 globulins. Tuberculin tests were negative.
Treatment with cephalothin (6 gm every 24 hours) and gentamicin (320 mg every 24 hours) had no effect clinically.
Treatment with betamethasone, 4 mg per day, was then initiated. A few days later the patient's mental state cleared and a
deep amnesic syndrome (to be described later) was observed.
The patient's temperature returned to normal. Betamethasone was gradually tapered beginning on November 10,
197 1. Subsequently the patient became confused again for
several days and a generalized epileptic seizure occurred on
December 3 , 1971. EEG did not show any focal signs. The
patient complained of diffuse arthralgias and intense abdominal pain. Deep tendon reflexes were abolished. Electromyography showed signs of denervation. Quadriceps biopsy
did not show any vasculitis or denervation atrophy. Betamethasone treatment (4 mg/day) was resumed on January
5, 1972. The amnesic syndrome was prominent by then and
remained unchanged until his death 20 months later. On
June 1, 1972, an inguinal lymphadenopathy was discovered.
O n histological examination, Hodgkin's disease (LukesReyes type 2) was diagnosed. There was diffuse involvement
of the lymphatic system and liver. A second generalized
epileptic seizure occurred on July 6, 1972. Chemotherapy
was started on June 25, 1972, and included procarbazine,
Received Nov 19. 1984. and in revised form Feb 18. 1985. Accepted for publication Feb 19, 1985.
Address reprint requests
Dr Duyckaerts,
chlormethine chlorhydrate, and vincristine sulfate. The patient died of Hodgkin’s disease on September 3, 1973.
Behavioral Changes
The patient’s memory deficit remained unchanged from January 1972 until his death 20 months later. Anterograde amnesia was of exceptional intensity: the patient could not remember events in the hospital from one moment to the next
and kept asking the same questions. H e could not recognize
his physicians and the patients around him. He greeted people who had left his room a few minutes earlier as if he were
seeing them for the first time. He sometimes stated that he
had already seen one of his nurses or fellow patients but was
never able to remember the person’s name or the moment
when they had possibly met. The intense abdominal pains
from which he continued to suffer were also forgotten and
he could not remember having the injections for their relief.
The patient had forgotten the initial sinus puncture but could
describe his work in Senegal and the topography of the
places where he lived. H e could recall the names of people
he knew there as well as the names of his schoolmasters and
events which occurred when he was studying theology. H e
knew his father’s birthdate as well as those of his two sisters.
He was able to say mass and recite his prayers and to recognize old friends and family members. H e could comment on
important political events which took place 3 years before his
illness. The patient was never able to hold a conversation and
was acutely conscious of his memory deficit. H e was disoriented in time and although he could sometimes state the
correct year, he never knew the month, season, or day of the
week. He knew that he was in Paris and could sometimes
remember that he was in the Salp@trit.reHospital. H e was
able to find his way to his room and from his room to the
toilets. However, when he awakened in the morning, he
would realize he was in a hospital but was not sure whether
he had been there the day before. During his hospital stay,
the patient appeared placid and spent much of his time doing
and undoing the same jigsaw puzzle.
NezlropsychologicaL Testing
The patient was fully alert and cooperative during neuropsychological testing. Language, praxis, and gnosia abilities were
normal. Raven’s Progressive Matrix (PM 38) showed the
patient’s I Q to be 113. His I Q was 113 on Binois Pichot’s
synonyms test. Copying of Rey’s complex figure was normal.
Wechsler’s memory battery showed his MQ to be 74. The
patient could repeat immediately six digits or six words. H e
could also recall immediately the arrangement of six pictures
on a grid containing six squares after a presentation time of
15 seconds. When six colored tokens were presented successively in the same serial order, the patient could anticipate
the next colored token after three trials. These results were
within the normal range [17). Recognition (in the visual,
tactual, or verbal modes) was impossible as soon as an interfering task (counting backward) was undertaken. When requested to learn a list of ten words, the patient could recall
only the last three. He could repeat a series of three words
after one minute (without an interfering task) but if a new
series was added he immediately forgot the first three words.
He never mixed words of two successive series of three
words and he never added extra words.
Pathological Examination
Postmortem examination was performed 24 hours after
death. Hodgkin’s disease (lymphocyte depletion with abundant proliferation of Reed-Sternberg cells) involved the cervical, axillary, inguinal, hepatic, splenic, and aortic node
groups. The spleen (weight, 3 10 gm) and liver (weight, 2000
gm) were infiltrated by the same tumoral process. Gross
examination of the brain (weight, 1500 gm) showed bilateral
atrophy of the cornu Ammonis.
Microscopic examination of the brain showed almost complete neuronal loss (with prominent fibrillarygliosis) that was
restricted to the hippocampus and amygdala. Inflammatory
infiltrates were notably absent. Rod cell microglial proliferation, inclusion bodies, tumoral infiltration, and spongiosis
were not present. The meninges and vessels were normal. In
the hippocampus pyramidal cells had disappeared; only a few
neurons showing “ischemic cell changes” remained in field
H 2 (corresponding to CA2, CA3a and CA3b in the terminology of Lorente de Ni, [bl)(Fig 1). The dentate gyrus,
subiculum, and whole parahippocampal gyrus (including the
presubiculum and entorhinal area) were unaffected. The perforant path, alveus, and fimbria were normal. The fornix was
normal in size and well myelinated. In the amygdaloid body
(Fig 2), the basolateral parts of both nuclei were affected.
The medial nucleus was only partially damaged on the right
side. The stria terminalis was not atrophic and appeared normal. The other structures of the limbic system (mamillary
bodies; anterior, laterodorsal, and mediodorsal nuclei of the
thalamus; septal nuclei; cingular cortex) were unaffected.
The temporal stem was normal. The nucleus basalis of Meynert and brainstem were normal.
Discussion
The cause of the pathological changes noted in the
patient remains unknown. Ischemia can selectively destroy neurons of the CA1 sector of the hippocampus
in experimental animals 116, 267. Amygdaloid bodies
can also be involved 147. However, the patient’s clinical history does not provide clear evidence of an episode of cardiovascular failure. Epilepsy even in the
absence of hemodynamic changes can be responsible
for hippocampal lesions in animals (18, 191 and in
human subjects 1217. Delay and colleagues 1117 reported a case of deep amnesia following status epilepticus. Lesions were confined to the hippocampus and
spared the amygdaloid bodies. In our patient, two
epileptic seizures occurred after the onset of amnesia.
The occurrence of limbic encephalitis of the type described by Corsellis and associates [8} has been reported in Hodgkin’s disease. The pleocytosis and increase of globulin content in the cerebrospinal fluid
and the association with peripheral neuropathy are also
consistent with this diagnosis 18, 28). Regressive memory loss has been mentioned in a case of Hodgkin’s
disease that was not anatomically documented 151.
Histological changes which were noted in our case
were not inflammatory. However, perivascular cuffings
and glial nodules are sometimes very sparse in limbic
Duyckaerts et al: Amygdalohippocampal Amnesia
3 15
A
\
CGL
I
‘L7m
c
D
E
F
Fig I , Outlines of hippocampal lesions on coronal sections. (A)
L.ft side at the level of the optic tract (OT).(B) Right side at
the level of the optic tract. (C)Left side at the level of the corpus
geniculatum laterale (CGL). (0)Right side at the level of the
CGL. (A = complete neuronal loss; A = incomplete neuronal
loss.) (E) Coronal section of the ldt hippocampus at the level of
the corpus geniculatum mediale. (Loyez stain; x 3.5 before 5%
reduction.) The alveus (small arrowheads) remains well myelinated. (F) Coronal section of the right hippocampus at the level of
the CGL. Complete neuronal loss in Rose’sfield H I is seen
(large arrowheads). (Nisslstain; x 10 before 5% reduction.)
316 Annals of Neurology Vol 18 No 3 September 1985
/
.- -
c
/
/
A
I
€3
\
(
\
D
E
.
I
I
A
.-- -
F
Fig 2. Outlines of the lesions of the amygdzloid bodies on coronal
sections. (A, C lejl hemisphere; B, D right hemisphere;A, B
anterior level; C, D posterior level. (A = complete neuronal loss;
A = incomplete neuronal loss; 0 = “ischemzccell changes.”)(E)
Coronal section of the left amygdzloid body at the level of the
optic tract showing atrophy of the amygdaloid body. (Loyez
stain; x 4.3 before 5 % reduction.) (F)Gliosis and neuronal loss
in the basokzteral part of the amygdaloid body. (HGE; x 80
bebve 5% reduction.)
Duyckaerts et al: Arnygdalohippocampal Amnesia
3 17
encephalitis [28}. Long-term sunrival could hypothetically lead to spontaneous healing of the encephalitis,
leaving neuronal loss and gliosis as late sequelae.
In the final analysis, no definite conclusion could be
drawn about the cause of our patient’s disease. The
essential features of the amnesic syndrome were as
follows: remarkably intense forgetting in recall tasks as
well as in recognition tasks, sparing of immediate
memory and immediate processing of information,
sparing of memories preceding the illness, acute
awareness of the memory deficit, and absence of confabulation. New information could be processed normally within the range of his attention span. This type
of amnesic syndrome is quite similar to that of another
patient who developed deep amnesia after bilateral resection of the medial pans of the temporal lobes 1241;
it is now recognized as a characteristic amnesia resulting from bilateral temporal lesions [1?, 2 51. Anatomical examination of the patient described here showed
bilateral temporal neuronal loss and gliosis limited to
the cornu Ammonis and amygdaloid bodies. The fornix was well myelinated and the mamillary bodies and
the anterior and laterodorsal nuclei of the thalamus
were not affected; the absence of secondary changes in
these structures has already been alluded to when hippocampal lesions are limited and do not include the
subicular area {23). This is in accordance with experimental evidence that shows the principal efferents of
the hippocampus come from the subicular area {2?).
Medial temporal lesions causing permanent global amnesia are bilateral in all documented cases [14]. Determination of the critical structures remains a subject of
controversy, however. Horel [15) claimed that the major part of the temporal lobe was involved in bitemporal amnesia, either directly or indirectly by way of a
disconnection resulting from temporal stem lesions.
Present evidence, both experimental 1321 and clinical
f l l , 28, present case), does not support this claim. In
all reported cases the lesions involved the hippocampus and in two cases {I 1, 28) they were the only structures involved. All the other reports mention lesions
in other structures {3, 7, 9 , 22, 29, 30, 31). In our
patient, the only associated lesion was located in the
amygdaloid bodies. The clinical consequences of
amygdaloid involvement are only partially known {I}.
When the amygdaloid bodies are affected in viral encephalitides [2, 12, 131, rhe disease is accompanied
by considerable cortical destruction and the specific
roles of the amygdaloid bodies are impossible to establish. In hippocampectomized monkeys, Mishhn 120)
showed that amygdaloid lesions led to an increase in
the recognition deficit. These lesions could play a part
in human amnesia but clinical data at hand are not yet
conclusive. It is indeed not known if restricted lesions
of the hippocampus (sparing the amygdala) cause a less
318 Annals of Neurology
Vol 18 No 3
severe amnesia than that observed in the patient described here and the one reported earlier 1241.
An abstract of this paper was presented at the IXth International
Congress of Neuropathology (Vienna, September 5-10, 1982) and
at the annual meeting of the European Brain and Behavior Society
(Marseille, September 23-24, 1983).
We thank C. Raton, J. Coestesquis, and N. C. Foenix for histological work, M. Battisacchi and J. Bethermin for secretarial assistance,
and P. Miele for photographical work. We are indebted to Dr Baron
for correcting the English manuscript.
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Corrections
In abstracts D1 and P174 by Argov and associates on pages
119 to 120 and 162, respectively, of the Program and Abstracts of the American Neurological Association (Ann
Neurol Vol 18, 1985), reference to 31P magnetic resonance
imaging should be changed to " P nuclear magnetic resonance
spectroscopy throughout. This includes listing of the abstract
titles and authors in the Program on pages 114 and 116 in
the same issue of the Annals. Our apologies to the authors
for this error.
In abstract P153 (Ann Neurol Vol 18, 1985), please add
Neil Cashman as the first author, both in the Program on
page 114 and the Abstracts on page 157. Our apologies to
the authors for this oversight.
Duyckaerts et al: Amygdalohippocampal Amnesia
3 19
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