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CLINICAL CASE SEMINAR
Central Diabetes Insipidus due to Cytomegalovirus
Infection of the Hypothalamus in a Patient with
Acquired Immunodeficiency Syndrome: A Clinical,
Pathological, and Immunohistochemical Case Study
ARNOLD M. MOSES, DAFYDD G. THOMAS, MARIE C. CANFIELD,
Departments of Medicine (A.M.M., M.C.C.) and Pathology (D.G.T., G.H.C.), SUNY Upstate Medical University, Syracuse,
New York 13210
We report a case of central diabetes insipidus (CDI) in a pa-
tient with AIDS due to cytomegalovirus (CMV) infection of the
vasopressin-producing areas of the hypothalamus. The clini-
cal diagnosis is established by definitive clinical and labora-
tory evidence of CDI. Detailed histopathological and immu-
nohistochemical studies establish CMV as the causative agent
and demonstrate the deficit of vasopressin in the synthesizing
O PPORTUNISTIC INFECTIONS INVOLVING the en-
docrine organs in patients with AIDS have been in-
creasingly recognized (1). Cytomegalovirus (CMV) is the
most frequent organism involved (2– 6). Abnormalities of the
adrenals, testes, thyroid, and anterior pituitary have received
the most attention. In contrast, endocrine disorders associ-
ated with the hypothalamo-neurohypophysial system have
received scant attention.
Central diabetes insipidus (CDI) is a disorder character-
ized by hypotonic polyuria due to the lack of vasopressin
(AVP). AVP is normally synthesized by the magnocellular
neurons of the paraventricular and supraoptic nuclei of
the anterior hypothalamus. The hormone migrates down the
axons that extend through the posterior pituitary stalk to the
posterior pituitary (neurohypophysis), where it is stored and
eventually released into the circulation. To date, there has
been only one report of two patients with AIDS and CMV
infection who had clinical evidence of deficient function of
the hypothalamic neurohypophysial system (7). These pa-
tients presented with adipsic hypernatremia with inappro-
priately low plasma levels of AVP. An autopsy was per-
formed on one of these patients and revealed “necrotizing
periventricular and hypothalamic CMV encephalomyelitis
and secondary hemorrhage.” There were no further details.
This report is of a case of AIDS who developed CDI due
to CMV infection of the AVP-producing areas of the hypo-
thalamus. We obtained definitive clinical evidence of CDI,
along with detailed histopathological and immunohisto-
Abbreviations: AVP, Vasopressin; CDI, central diabetes insipidus;
CMV, cytomegalovirus; MR, magnetic resonance.
51
The Journal of Clinical Endocrinology & Metabolism 88(1):51–54
Copyright © 2003 by The Endocrine Society
doi: 10.1210/jc.2002-020879
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AND GEORGE H. COLLINS
neurons. Physicians caring for patients with AIDS should be
aware of CDI and adipsic hypernatremia as potential compli-
cations of CMV infection. The case also demonstrates that
patients with diabetes insipidus do not have polyuria when
glucocorticoid deficiency coexists. (J Clin Endocrinol Metab
88: 51–54, 2003)
chemical studies that demonstrate the AVP deficiency and
establish CMV as the etiological agent.
Case Report
A 39-yr-old male was admitted to University Hospital
(Syracuse, NY) with nausea, vomiting, abdominal pain, light-
headedness on standing, and weight loss. He was known to
have AIDS, and his most recent CD4 lymphocyte cell count
was 13 cells/␮l. He reported previous iv drug abuse and
denied recent head trauma. Medications on admission in-
cluded trimethoprim/sulfamethoxazole and ibuprofen. He
appeared cachectic and dehydrated and had orthostatic hy-
potension. Endoscopy revealed a duodenal ulcer, 2 cm in
diameter. Laboratory studies included a 10% eosinophilia.
Serum sodium concentration was 130, and potassium was 5.6
mmol/liter. Urine-specific gravity was 1.014. Thyroid func-
tion tests were normal. Blood testosterone was low at 89
ng/dl (3.06 nmol/liter) when FSH and LH were inappro-
priately low at 2.0 and 6.0 mIU/ml (2.0 IU/liter and 6.0
IU/liter, respectively). GH was undetectable whereas pro-
lactin was elevated at 25.7 ng/ml (25.7 ␮g/liter).
Addison’s disease was established by failure of cortisol or
aldosterone levels to increase appropriately during the in-
fusion of 250 ␮g cosyntropin over 6 h. During that time,
plasma cortisol rose from 3.3 to 7.2 ␮g/dl (91.05 to 198.6
nmol/liter) whereas aldosterone levels rose from undetect-
able to 1.6 ng/dl (44.4 pmol/liter). Before the infusion, serum
ACTH was elevated to 74 pg/ml (16.3 pmol/liter). Last,
pathology later revealed gross and microscopic evidence of
adrenal atrophy with microscopic evidence of necrosis and
intracellular viral inclusions. Steroid replacement therapy
was instituted. Shortly thereafter, the patient developed hy-
52 J Clin Endocrinol Metab, January 2003, 88(1):51–54 Moses et al. • Clinical Case Seminar

potonic polyuria with urine volumes of approximately 9

liters/d. This was associated with intense thirst and elevation
of the serum sodium concentration to 149 mmol/liter with
urine osmolalities of 71 and 88 mmol/kg. A diagnosis of CDI
was confirmed by failure of antidiuresis with urine osmo-
lality 102, and with urinary AVP remaining undetectable
when plasma osmolality reached 306 at the end of a 2-h,
15-min infusion of 3% saline at the rate of 0.05 ml/kg䡠min (8).
He was thirsty throughout the infusion. The diagnosis was
further confirmed by the absence of the normally observed
hyperintense signal of the neurohypophysis on appropriate
T1-weighted magnetic resonance (MR) imaging of the neu-

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rohypophysis (9). In response to treatment with desmopres-
sin (10 ␮g twice daily by nasal spray), urine volumes de-
creased to 2–3 liters per day.
The patient died several weeks later secondary to small
bowel perforation and sepsis. Postmortem examination re-
vealed CMV infection involving multiple organ systems,
including the hypothalamus and posterior pituitary.

Materials, Methods, and Results

The determination of the absence of the normal hyperin-
tense signal of the neurohypophysis was done using T1-
weighted MR imaging equipment (General Electric SIGNA,
Syracuse, NY) of high field strength (1.5 T). Sagittal spin-echo
midline images with T1-weighted time parameters were ob-
tained with a 256 ⫻ 256 matrix, two signal acquisitions, and
a field of view of 18 cm. The section thickness was 3 mm, with
a 1-mm intersection gap (9). The remainder of the MR ex-
amination revealed mild diffuse atrophy of the brain and a
subtle nonspecific increased signal projected over the me-
dulla of unclear significance.
The autopsy was performed 24 h postmortem. The major
autopsy findings consisted of multiple areas of ulceration
and necrosis affecting lung, stomach, small intestine,
spleen, and adrenal glands. In all these areas, cells with
intranuclear and intracytoplasmic bodies were found, con-
sistent with CMV.
The brain and pituitary gland were examined after fixation
in buffered formalin. No gross abnormalities were noted.
Microscopic examination was also negative, except for the
paraventricular areas of the hypothalamus, which contained
histological changes consistent with CMV infection. The area
affected extends from the immediate retrochiasmatic region
to the mammillary body (Fig. 1). Throughout this region of
hyperemia and edema is a low-grade lymphocytic cellular
reaction. In the approximate location of the paraventricular
nucleus, large granular neurons are identified within which
intranuclear and intracytoplasmic inclusions are seen (Fig. 2).
Similar cells are less frequently noted in the premammillary
area. Immunohistochemical staining for CMV was per-
formed using a mouse monoclonal anti-CMV antibody that
is specific for proteins of the glycine-extracted CMV antigen
and is nonreactive to herpes viruses or adenoviruses. As
shown in Fig. 2, there is reaction product in the affected
neurons of the periventricular region as well as in the pars
nervosa and pars intermedia of the pituitary gland.
Immunohistochemical staining for AVP and oxytocin
showed a marked reduction in the number of cells stained in
FIG. 1. A photomicrograph of a sagittal brain section showing the
anatomical region from the lamina terminalis (arrowhead) anteriorly,
to the anterior hypothalamus (*) posteriorly, and the pathologically
affected region (between the arrows). III, Third ventricle; OCT, optic
chiasm and tract (magnification, ⫻4).
the paraventricular nucleus when compared with normal
control (Fig. 3). Staining that was randomly distributed oc-
curred on cell processes. Sections of the posterior pituitary
were only faintly positive for either AVP or oxytocin.
Discussion
CMV infection occurs frequently in patients with AIDS,
and multisystem disease, as occurred in our patient, is not
uncommon. In fact, CMV is the most common pathogen
involving the endocrine organs of patients with AIDS and
has been reported to involve virtually every organ system.
Clinically significant dysfunction, however, occurs less often
than does pathological evidence of infection. This is most
notable in the adrenal glands where CMV infection seems to
be much more frequent than are reports of adrenal insuffi-
ciency (1, 2, 10).
Less well documented is the association of CMV with
dysfunction of the hypothalamus or posterior pituitary.
Aside from the two cases described in the Introduction, we
have found only one report of five HIV seronegative infants
who developed CDI in association with CMV infection (11).
There have been several postmortem studies of CMV in-
volvement of the pituitary. One study involving 49 AIDS
patients found anterior pituitary involvement in five cases
and posterior pituitary involvement in two cases (12). In
another autopsy series, CMV in the anterior pituitary was
Moses et al. • Clinical Case Seminar J Clin Endocrinol Metab, January 2003, 88(1):51–54 53

FIG. 2. Three photomicrographs demonstrating CMV pathology. The left photo is from a section of hypothalamus stained with hematoxylin
and eosin (magnification, ⫻100). The middle photo is from an adjacent section immunohistochemically stained for CMV (magnification, ⫻100).

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The right photo is from a section of posterior pituitary stained immunohistochemically for CMV (magnification, ⫻40).

FIG. 3. Photomicrographs demonstrating the pathological effect of CMV infection on the function of cells in the paraventricular nucleus. The
left and middle photos are from a section of normal hypothalamus stained immunohistochemically for oxytocin and AVP, respectively. The right
photo from this patient shows the absence of immunostaining for AVP in cells of the paraventricular nucleus (magnification, ⫻100).

found in 3 of 88 AIDS patients (13). Examination of the
posterior pituitary revealed microglial nodules, which can be
caused by CMV, in 5 of the 88 studies, but inclusions were
not identified. CMV of the anterior but not posterior pituitary
was also reported in a series of 111 AIDS patients (14).
Reichert et al. (5), however, reported a case in which CMV
inclusions were identified in the posterior pituitary. In none
of these studies was the histopathology of the hypothalamus
described nor was there significant functional data available.
Thus, the current case is the first to have clinically docu-
mented CDI with definitive pathological evidence of infec-
tion of the AVP (oxytocin)-producing areas of the hypothal-
amus with CMV.
Our patient had a marked reduction of cells in the para-
ventricular nucleus, which stained for AVP. Lipsett et
al. (15) reported in 1956 that only a small percentage of AVP-
producing cells need to function to prevent the symptoms of
CDI. The diagnosis of CDI was established after the patient
was treated with hydrocortisone by his excretion of dilute
urine with elevated serum sodium and plasma osmolality.
The diagnosis was confirmed by undetectable urine AVP
excretion when blood was hypernatremic and hypertonic (8,
16, 17). Final confirmation of CDI was his antidiuretic re-
sponse to desmopressin and the absence of the normal hy-
perintense signal of the neurohypophysis on MR imaging (9).
Pathological confirmation of CMV infection involving hy-
pothalamic and posterior pituitary structures is also well
documented. The paraventricular nuclear involvement is es-
tablished by the presence of inflammation associated with
typical CMV-positive intranuclear inclusions in a nuclear
group lying adjacent to the third ventricle. The histological
characteristics of this nucleus are typical of the paraventricu-
lar nucleus, and the immunohistochemistry demonstrates
AVP in some of the unaffected neurons. The significance of
the CMV reaction product in the pars intermedia and distalis
is not clear because its histological location is not well doc-
umented, and there was no associated inflammatory reac-
tion. Localization within axons seems very probable because
of the histological appearance and would be indicative,
therefore, of transport through the supraopticohypophyseal
tract.
This patient presents one other aspect of this overall prob-
lem that is of clinical interest. His adrenal insufficiency, a
consequence of his CMV infection, masked the presence of
AVP deficiency because it was not until he was treated with
a glucocorticoid that he developed polyuria. The masking of
diabetes insipidus by glucocorticoid deficiency has been rec-
ognized for many years (18, 19), and the inability of patients
with cortisol insufficiency to excrete dilute urine is well
known (20, 21). The mechanism by which glucocorticoids
facilitate the excretion of solute free water has been the focus
of considerable debate. Suffice it to say, glucocorticoids can
undoubtedly inhibit AVP release (22–26). However, in cases
like this when AVP is absent, the aquaretic action of cortisol
is due to its action on decreasing the water permeability of
the distal nephron (24, 27). AVP deficiency may, therefore,
occur more often than is currently recognized if there is un-
recognized and untreated concurrent adrenal insufficiency.
Acknowledgments
We thank the nursing staff of the Clinical Research Unit, University
Hospital, for conducting the clinical studies on this patient. We also
thank Dr. S. Menchel (Onondaga County, NY, Medical Examiner’s of-
fice) for help with this case, J. Daucher for expert help in performing the
immunohistochemistry, and Bill and Jeff Stangenderg of INCSTAR
Corp. (Stillwater, MN) for the kind gift of antibodies to AVP and
oxytocin.
54 J Clin Endocrinol Metab, January 2003, 88(1):51–54
Received June 5, 2002. Accepted September 30, 2002.
Address all correspondence and requests for reprints to: Arnold M.
Moses, M.D., Institute for Human Performance, Room 1264, University
Hospital, 750 East Adams Street, Syracuse, New York 13210. E-mail:
mosesa@upstate.edu.
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