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CLINICAL CASE SEMINAR |
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
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{at}upstate.edu.
Abstract
We report a case of central diabetes insipidus (CDI) in a patient with AIDS due to cytomegalovirus (CMV) infection of the vasopressin-producing areas of the hypothalamus. The clinical diagnosis is established by definitive clinical and laboratory evidence of CDI. Detailed histopathological and immunohistochemical studies establish CMV as the causative agent and demonstrate the deficit of vasopressin in the synthesizing neurons. Physicians caring for patients with AIDS should be aware of CDI and adipsic hypernatremia as potential complications of CMV infection. The case also demonstrates that patients with diabetes insipidus do not have polyuria when glucocorticoid deficiency coexists.
OPPORTUNISTIC INFECTIONS INVOLVING the endocrine organs in patients with AIDS have been increasingly recognized (1). Cytomegalovirus (CMV) is the most frequent organism involved (2, 3, 4, 5, 6). Abnormalities of the adrenals, testes, thyroid, and anterior pituitary have received the most attention. In contrast, endocrine disorders associated with the hypothalamo-neurohypophysial system have received scant attention.
Central diabetes insipidus (CDI) is a disorder characterized 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 patients presented with adipsic hypernatremia with inappropriately low plasma levels of AVP. An autopsy was performed 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 hypothalamus. We obtained definitive clinical evidence of CDI, along with detailed histopathological and immunohistochemical 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, lightheadedness on standing, and weight loss. He was known to have AIDS, and his most recent CD4 lymphocyte cell count was 13 cells/µl. He reported previous iv drug abuse and denied recent head trauma. Medications on admission included trimethoprim/sulfamethoxazole and ibuprofen. He appeared cachectic and dehydrated and had orthostatic hypotension. 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 function tests were normal. Blood testosterone was low at 89 ng/dl (3.06 nmol/liter) when FSH and LH were inappropriately low at 2.0 and 6.0 mIU/ml (2.0 IU/liter and 6.0 IU/liter, respectively). GH was undetectable whereas prolactin was elevated at 25.7 ng/ml (25.7 µg/liter).
Addison’s disease was established by failure of cortisol or aldosterone levels to increase appropriately during the infusion of 250 µg cosyntropin over 6 h. During that time, plasma cortisol rose from 3.3 to 7.2 µg/dl (91.05 to 198.6 nmol/liter) whereas aldosterone levels rose from undetectable 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 hypotonic 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 osmolality 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·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 neurohypophysis (9). In response to treatment with desmopressin (10 µg twice daily by nasal spray), urine volumes decreased to 2–3 liters per day.
The patient died several weeks later secondary to small bowel perforation and sepsis. Postmortem examination revealed CMV infection involving multiple organ systems, including the hypothalamus and posterior pituitary.
Materials, Methods, and Results
The determination of the absence of the normal hyperintense 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 obtained with a 256 x 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 examination revealed mild diffuse atrophy of the brain and a subtle nonspecific increased signal projected over the medulla 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, consistent 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 performed 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.
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). Staining that was randomly distributed occurred on cell processes. Sections of the posterior pituitary were only faintly positive for either AVP or oxytocin.
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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 insufficiency (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 involvement 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 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 documented CDI with definitive pathological evidence of infection of the AVP (oxytocin)-producing areas of the hypothalamus with CMV.
Our patient had a marked reduction of cells in the paraventricular nucleus, which stained for AVP. Lipsett et al. (15) reported in 1956 that only a small percentage of AVPproducing 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 response to desmopressin and the absence of the normal hyperintense signal of the neurohypophysis on MR imaging (9).
Pathological confirmation of CMV infection involving hypothalamic and posterior pituitary structures is also well documented. The paraventricular nuclear involvement is established 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 paraventricular 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 documented, and there was no associated inflammatory reaction. 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 problem 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 recognized 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, 23, 24, 25, 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 unrecognized 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 office) 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.
Footnotes
Abbreviations: AVP, Vasopressin; CDI, central diabetes insipidus; CMV, cytomegalovirus; MR, magnetic resonance.
Received June 5, 2002.
Accepted September 30, 2002.
References
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