Acta Neuropathol (1990) 80: 8 5 - 87
Acta
Short original communications
Necrosis of granule cells of hippocampus in adrenocortical failure
J. Ma~hlen and A. Torvik
Division of Neuropathology, Department of Pathology, Ullev~tlUniversity Hospital, N-0407 Oslo 4, Norway
Received September 8, 1989/Revised, accepted January 12, 1990
Summary. A case o f u n t r e a t e d a n d r a p i d l y progressive
A d d i s o n ' s disease in a 23-year old w o m a n showed selec-
tive necrosis with k a r y o r h e x i s o f the g r a n u l e cells in the
h i p p o c a m p u s . We suggest t h a t this u n i q u e lesion was
caused by a severe a d r e n o c o r t i c a l insufficiency. This
e x p l a n a t i o n is in a c c o r d a n c e with a recent r e p o r t of selec-
tive loss o f h i p p o c a m p a l g r a n u l e cells after complete
a d r e n a l e c t o m y in rats. N o evidence o f nerve cell loss
was f o u n d in three cases of A d d i s o n ' s disease t h a t h a d
received cortisone t r e a t m e n t , which is c o n s i s t e n t with the
e x p e r i m e n t a l o b s e r v a t i o n t h a t even very low levels of
cortisone in a d r e n a l e c t o m i z e d rats are sufficient to pre-
vent g r a n u l e cell loss.
Key words: A d d i s o n ' s disease - A d r e n o c o r t i c a l fail-
ure - Neuropathology
A recent r e p o r t described a n e a r l y complete a n d selective
loss o f g r a n u l e cells in the h i p p o c a m p u s in a d u l t rats 3 to
4 m o n t h s after complete a d r e n a l e c t o m y [4]. The a u t h o r s
c o n c l u d e d t h a t the a d r e n a l glands play a role in m a i n t a i n -
ing the s t r u c t u r a l integrity of certain parts o f the n o r m a l
a d u l t brain. This o b s e r v a t i o n led us to r e e x a m i n e the
h i p p o c a m p u s in four cases o f A d d i s o n ' s disease t h a t were
collected f r o m the a u t o p s y files. O n e of them, a case o f
r a p i d l y progressive a n d clinically u n d i a g n o s e d disease,
showed a selective necrosis with karyorhexis o f the g r a n -
ule cells of the h i p p o c a m p u s .
Case reports
Case 1
Clinical history. This 23-year-old previously healthy woman gradu-
ally developed increasing weakness, anorexia and weight loss from
Offprint requests to: J. M~ehlen (address see above)
Heuropathologlca
9 Springer-Verlag1990
early summer, 1984. From mid-September her condition deterio-
rated rapidly, and she was admitted in shock with a blood pressure
of 65/50 and a pulse of 130. Her temperature was 38.8~ Her
skin was hyperpigmented and Addison's disease was suspected but
considered unlikely because her serum electrolytes were nearly nor-
mal (Na 134 mmol/1, K 5.1 mmol/1). In retrospect, the normal so-
dium value was probably due to dehydration. Blood sugar was
elevated to 21 mmol/1 and she had ketonuria. Septicemia and dia-
betes were considered the most likely diagnoses. She died 12 h after
arrival in hospital.
Hormone analyses, the results of which became available after
her death, give values for cortisol and aldosterone which were
too low to be quantified (< 30 nmol/1 and < 80 pmol/1, respec-
tively).
General autopsy. Both adrenals were extremely atrophic and had a
total weight of 3 g. Microscopically, the adrenal cortex was replaced
by a vascular connective tissue with dense infiltrates of lymphocytes
and plasma celis. There were hardly any adrenocortical cells left.
The thyroid gland also showed a marked focal mononuclear inflam-
mation. The pituitary gland and the pancreas were normal. There
was no inflammation of the pancreatic islets. The other major inter-
nal organs were also normal.
The brain weighed 1550 g. No gross lesions were seen. Micro-
scopic sections were available from the hippocampus, frontal cortex,
basal ganglia, thalamus, mesencephalon, pons, medulla and cerebel-
lum. The only abnormaiity was seen in the hippocampus where
numerous necrotic neurons with karyorhexis were scattered
throughout the entire extent of the granular layer (Fig. 1). There
was no microgliaI or astroglial reaction in the granular layer. There
was no indication of anoxic cell damage or other diseases in the
brain.
Cases 2 - 4
The main findings in these cases are presented in Table 1. They all
had clinically diagnosed and necropsy-proven Addison's disease of
several years' duration and they all had received more or less ad-
equate cortisone treatment. Case 2 had episodes of Addisonian crisis
due to inadequate medication. All cases had an extreme atrophy of
the adrenals and nearly complete loss of adrenocortical cells. None
of them showed nerve cell loss or gliosis of the granular layer of the
hippocampus. The cause of death was uncertain in cases 2 and 3
(see Table 1).
86

Table 1. Main data fl'om the four examined cases of Addison's disease

Case no. Sex Age at Duration Treatment Cause of death

death of symptoms

1 Female 23 5 months - Adrenocortical failure

2 Male 38 20 years Corticosterone Adrenocortical failure?"
3 Male 37 Several years Corticosterone Adrenocor tical failure?b
4 Male 26 8 years Corticosterone Subependymona of IVth ventricle

" Psychiatric case. Irregular cortisone treatment. Died a few hours after arrival in hospital
b Found dead in bed. No convincing cause of death was found

for the neuronal group involved and for the type of

Fig. 1. A Three karyorhectic neurons in the granule cell layer of the
hippocampus from case I (arrows). B Distribution of the necrotic
neurons in the granule cell layer indicated by black circles in a
representative section from the hippocampus. A, B H&E; A • 950,
B •
neuronal degeneration.
The granule cells of the hippocampus show consider-
able resistance to injury and, to our knowledge, isolated
loss of granule cells in the area dentata has not been
previously described in man. The granule cells may be
injured together with other parts of the hippocampus in
hypoglycemia [1]. However, our case had a hyperglycemia
which probably was due to a simultaneous juvenile
diabetes. Moreover, no cell injury was observed in
the rest of the hippocampus or other parts of the
brain.
Recently, Sloviter et al. [4] described a selective and
nearly complete loss of nerve cells in the area dentata 3
to 4 months after complete bilateral adrenalectomy in
rats. They also showed that the lack of glucocortical
hormones was the crucial factor in this lesion. We suggest
a similar mechanism for the selective granule cell destruc-
tion in our case 1.
The type of neuronal degeneration in our case was
also remarkable (Fig. 1). To our knowledge, karyorhexis
has not been observed in adult brains during neuronal
disintegration. In contrast, in the fetal and neonatal
periods it has been described in several conditions, such
as naturally occurring neuronal death [3] and following
anoxic damage [2]. The type of acute neuronal degener-
ation that occurs in adult rats after adrenalectomy [4] is
not known.
None of our three other cases of Addison's disease
showed evidence of acute or chronic nerve cell loss in the
hippocampus, although they had as severe destruction of
the adrenal cortex as case 1. However, as in rats, cortisone
treatment may have been sufficient to prevent the nerve
cell disintegration.
In conclusion, we suggest that the neuronal ka-
ryorhexis in the granule cell layer of the hippocampus in
our case I was due to severe adrenocortical failure. This
structure should be examined in other fatal cases of
Addison's disease.

Discussion

The patient we describe here (case l) died of an untreated

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