Diagnosis and Treatment

27 of Hypothalamic Disease

Marcello o. Bronstein, MO,

Malebranche B. C. Cunha Neto, MO,
and Nina Rosa de C. Musolino, MO

CONTENTS
INTRODUCTION
LESIONS LEADING TO HYPOTHALAMIC DYSFUNCTION
HYPOTHALAMIC SYNDROMES
SELECTED READINGS

1. INTRODUCTION hypothalamus affecting disorders (documented by

autopsy), neuroophthalmic involvement occurred in
Anatomo-functional studies on the hypothalamus
78% of cases, pyramidal or sensitive deficits in 75%
have faced major difficulties, because this organ can-
?eadache in 65%, extrapyramidal cerebellum sign~
not, as far as function is concerned, be considered
I~ 62%, vomiting in 40%, precocious puberty in 40%,
like the cerebral cortex, where the homunculus could
dIabetes insipidus in 35%, hypogonadism in 32%,
be mapped, with usually well-determined brain
sleepiness in 30%, dysthermia in 28%, and obesity
regions corresponding to somatic or visceral afferent
or edema in a further 25%. Most of these patients
or efferent projections, according to an established
had two or more of such symptoms concurrently.
map. This may be because of the proximity of the
However, some disorders are clinically represented
hypothalamic nuclei to afferent and efferent paths of
as restricted hypothalamic manifestations, such as
the cortex, thalamus, limbic system, and spinal cord;
precocious puberty or gelasmus convulsive crisis in
all occurring in a rather limited region, measuring 1.5
the case of hamartomas.
x. 1:5 x. 1.3 cm, weighing approximately 2.5 g and
Systemic signs and symptoms (therefore, not in
dIVIded mto three zones (peri ventricular, medial and
the hypothalamus) should be sought in diseases such
lateral) and four regions (preoptic, supraoptic, tuberal,
as sarco.idosis, histiocytosis, infections, porphyria,
and mamilIary.) In Table 1, we describe the several
metastatlc tumors, and lymphomas. Seldom are such
hypothalamic regions or nuclei involved in different
diseases restricted to the hypothalamus. Acute lesions,
functions, according to studies conducted both in
such as trauma or vascular accidents, generally lead
human beings and other animals.
to consciousness impairment, hyperthermia, and dia-
The hypothalamic syndromes have several etio-
betes insipidus, which may be transient should the
logic possibilities and clinical manifestations. Among
patient survive, whereas the more chronic diseases
60 patients reviewed by Bauer as suffering from
lead to cognitive impairment and endocrine disorders,
From: Neuroendocrinology in Physiology and Medicine, (P. M. Conn
usually irreversible. Table 2 depicts the main causes
and M. E. Freeman. eds.). © Humana Press Inc .. Totowa. NJ. of hypothalamic syndromes.

475
476 Part V / Neuroendocrinology

Table 1
Hypothalamic Regions
Function Nucleus or Region
CRH, TRH, Dopamine, Somatostatin, GnRH Paraventricular
Somatostatin, Dopamine, Proopiomelanocortin, Arcuate
GHRH
Vasopressin (ADH) Supraoptic and Paraventricular
Thirst Anterior and Lateral Preoptic Hypothalamus
Gain and Loss of Heat (Afferent Path) Anterior Preoptic Hypothalamus
Gain of Heat (Efferent Path) Posterior and Medial Hypothalamus
Loss of Heat (Efferent Path) Posterior and Lateral Hypothalamus
Sleep Anterior Hypothalamus
Wakefulness Posterior Hypothalamus
Sympathetic stimulus Posteromedial Hypothalamus
Parasympathetic stimulus Anterior Preoptic Hypothalamus
Emotion Ventromedial, Medial, Posterior, Caudal and Lateral
Hypothalamus
Memory Ventromedial, Mamillary and Medial-Dorsal
Urination and Evacuation Medial Tuberal Region
Gastrointestinal Motility Anterior Preoptical Hypothalamus and Posterior Dorso-
lateral Region

Table 2 benign, they may present malignant behavior accord-

Etiology of Hypothalamic Syndromes ing to their location and growth rate. By and large
Craniopharyngioma craniopharyngiomas account for approximately 2.5%
Germ Cell Tumor of brain tumors, and for 5 to 10% of children's brain
Hamartoma neoplasms. They can be cystic, solid, or mixed, either
Meningioma calcified or not. (Fig. lA and B).
Glioma Symptoms at onset depend both on the location
Chordoma and size of the lesion and patient age. Thus, such
Pituitary Tumor tumors may either lead to variable neurological and
Metastatic Tumor endocrine symptoms (Table 3) or just be an incidental
Dermoid and Epidermoid Tumor finding on an imaging examination.
GranulomatouslInftamatory Diseases
The incidence of partial or total hypopituitarism
• Sarcoidosis
is high as from diagnosis. Figure 2 illustrates the
• Histiocytosis X
• Tuberculosis frequency of such a deficiency in the several hypothal-
Radiation Lesion amus-pituitary sectors in patients bearing craniopha-
Traumatic Lesion ryngiomas, at diagnosis. Thus, patients diagnosed as
Other: Meningitis, Hydrocephalus, Laurence-Moon- having craniopharyngioma should have their hor-
Biedl and Prader-Willi Syndrome, Aneurysm, monal profile assessed in order to receive proper hor-
Arteriovenous Malformation, Wernicke's Disease, monal replacement, particularly glucocorticoid and
Aracnoid Cyst thyroid hormone, whose aim is to reduce surgical
treatment risks.
Image assessment should be performed by mag-
2. LESIONS LEADING TO netic resonance imaging (MRI) associated with com-
HYPOTHALAMIC DYSFUNCTION puted tomography imaging with no contrast agent, to
allow better identification of calcification.
2.1. Craniopharyngioma Initial craniopharyngioma treatment is almost
Craniopharyngiomas are neoplasms in the hypo- invariably surgical. Ideally, the lesion should be com-
thalamus-pituitary region, considered to arise from pletely removed (Fig. 3). However, as such procedure
Rathke's pouch remnants. Although histologically may be associated with high morbidity and mortality,
Chapter 27 / Hypothalamic Disease 477

Table 3
Clinical Presentation in 29 Patients
with Craniopharyngioma*
Headache 80%
Visual impairment 60%
Delayed puberty 44%
Growth arrest 40%
Diabetes insipidus 23%
Intracranial hypertension 23%
*Neuroendocrine unit, Division of Neurosurgery, Hospital
das Clinicas, University of S.Paulo.

1111)%

811%

60%

·UI%

20%

II
GH LH FSH TSH ACTH

Fig. 2. Hormonal fa ilure (%) before (0) and after (_ ) surgical

treatment for craniopharyngiomas (Neuroendocrine Unit,
Divi ion of eurosurgery, University of S.Paulo).

it is not unusual to combine partial resection with a

postsurgical radiation therapy. Surgical approach may
either be transsphenoidal or transcranial, with or with-
out endoscopy aid. Both the choice of approach and
treatment outcome depend mainly on the craniopha-
ryngioma initial features. Young age (under 5 yr),
presence of hydrocephalus, and giant tumors are asso-
ciated with a higher incidence of surgical and hypo-
thalamic complications.
Hormonal impairment is quite frequent after
surgery, associated or not with radiation therapy
(Fig. 2). Thus, patients should be reassessed following
treatment. However, it is a well-known fact that some
children show normal growth despite growth hormone
(GH) deficiency after surgery or radiation therapy.
The mechanism accounting for catch-up growth is
uncertain. It is assumed that improved feeding, with
resulting weight gain, may lead to increased serum
Fig. 1. Craniopharyngioma imaging: (A) Plain skull radiogra- insulin levels, a hormone that could be implicated in
phy showing suprasellar calcification. (B) MRI (T I weighted
such effect; other growth factors may also be
coronal view enhanced by gadolinium). (Bl) predominantly
cystic suprasellar lesion. A normal pituitary gland is observed involved. The importance of this effect has led to
(arrow). (B2) mixed (solid / cystic) sellar and suprasellar the discussion about indicating GH replacement on
tumor. clinical or laboratory basis.
478 Part V I Neuroendocrinology

male prevalence. Incidence of such tumors is 65 %

for germinomas, of a better prognosis, 5% for those
tumors of nongerminomal cells as embryonal carci-
noma, 5% for choriocarcinoma (worst prognosis), 7%
for yolk sac tumor, and 18% for teratoma (either
mature or immature). These tumors, which may be
mixed, represent totipotent germ cells that differenti-
ate into germ cells (germinoma), embryonic cells
(embryonal carcinoma and teratoma), and extra-
embryonary elements as yolk and trophoblastic sac
(choriocarcinoma). Cells originating germ cell neo-
plasms in the brain are unknown. Such cells may
be located in the suprasellar or pineal region and
sometimes a tumor is found in both sites. Teratomas
and choriocarcinomas occur more often in childhood,
whereas germinomas, embryonal carcinomas, tumors
of the yolk sac, and immature teratomas occur more
often in adolescents and young adults, with a male
gender prevalence.
Mixed tumors account for 50-60% of tumors. If
suprasellar, pure germinomas are the tumors most
often found, whereas the pineal ones are usually mixed.
The most frequent found clinical setting is that of
diabetes insipidus, visual loss, and hypopituitarism,
sometimes combined with hypothalamic syndromes
of dysfunction of appetite control and adipsia, hydro-
cephalus, somnolence, and Parinaud sign. Neurologi-
cal abnormalities are more typical in nongerminal
tumors, whereas the endocrine ones are more fre-
quently related to germinal tumors. Approximately,
5% of the latter develop precocious puberty, which
may occur because of median eminence compression
or hCG production in boys.
Beta-hCG and alpha-fetoprotein can be found both
in the blood and cerebrospinal fluid of patients with
germ cell tumors. Alpha-fetoprotein is produced by
yolk sac and fetal liver, being inhibited at birth, only
to reappear in patients hosting hepatocellular or germ
cell tumors with either a yolk sac or an embryonal
carcinoma component. Beta-hCG is produced by
giant syncytiotrophoblast cells, likely to be found in
patients with choriocarcinoma and nontrophoblastic
Fig. 3. CT coronal views of a cystic craniopharyngioma before tumors, as lung and stomach adenocarcinomas,
(A) and shortly after surgery (B). (C) MRI coronal view, 5
yr after surgery showing no tumor remnants and stalk displace-
hepatocellular carcinoma, and malignant melanoma.
ment (arrow). High level of alpha-fetoprotein indicates the presence
of germ, nongerminomal cells within the tumor,
whereas an increase in beta-hCG may occur both in
2.2. Germ Cell Tumors germinoma and in nongerminomal neoplasms. Ger-
Germ cell tumors account for 1.8% of primary minomas and teratomas are typically negative to both
brain tumors before 20 yr of age in the United States markers. Both markers may be useful to control
and 6.5% of all brain tumors in Japan; with incidence therapeutic success, tending to increase again if the
peaks in the second and third decades of life, and tumor recurs.
Chapter 27 I Hypothalamic Disease 479

to an actual precocious puberty in about 90% of

patients (Fig. SA and B). Some cases lead to preco-
cious puberty even with no GnRH immunoexpression,
presumably by compression with median eminence
stimulation or interruption of GnRH inhibitory fac-
tors. Such cases also show a gonadotropin positive
response following acute injection of the hypothala-
mic peptide. Moreover, hamartomas may lead to con-
vulsions, particularly of the gelasmus type, psycho-
motor delay, and emotional instability. Pallister-Hall
syndrome consists of hypothalamic hamartoblastoma;
face-skull, heart, renal, lung, and fingers abnormalit-
ies; imperforate anus; and hypopituitarism with
absence of both the anterior and posterior pituitary
gland. When the clinical setting points to precocious
puberty, as a rule GnRH analogs administration has
been the treatment of choice. Surgical management
is currently uncommon, as these tumors are slow-
growing and resection is usually followed by high
morbidity-mortality rates. Total excision may control
convulsive crisis.

2.4. Meningioma
Meningiomas account for one fourth of all brain
tumors. Peri pituitary meningiomas have their dural
origin in several sella-adjacent areas. Meningiomas
originate in meningoendothelial cells and arachnoid
villi. Female gender prevails and estrogen and proges-
terone receptors have been shown in some of these
tumors. Such evidences may be the link between the
Fig. 4. MRI (Tl weighted coronal view enhanced by gadolin- presence of meningioma and higher prevalence of
ium) of a seven years old girl with a biopsy proved germinoma, breast cancer in the same patient, as well as neurologi-
before (A) and after (B) radiotherapy. Important tumor reduc- cal impairment in meningioma patients during preg-
tion is observed. nancy or menstruation. Visual loss is the most prevail-
ing symptom, Foster-Kennedy syndrome may be
Some authors advocate the use of an initial radia- found in 7.2% of cases, i.e., one eye amaurosis with
tion therapy trial with a therapeutic dose of about ipsilateral optic disk atrophy and contralateral papi-
2000 cGy, based on the high germinoma sensitivity to lledema. Endocrine abnormalities occur in 22% of
such therapeutic modality. Others insist on obtaining patients, and mostly involve the anterior PItUitary
histologic diagnosis, by performing a tumor excision gland. Diabetes insipidus occurs in only 4.8% of
or biopsy alone in germinomas, followed by adjunc- patients.
tive radiation therapy (Fig. 4) or chemotherapy. In radiological semiology, hyperostosis at the
meningeal point of origin may appear on plain skull
2.3. Hamartoma radiography and computed tomography (CT); in some
Hamartomas are benign tumors composed of a cases, calcifications may be found. Both on CT and
blend of neurons, astrocytes, and oligodendrocytes, MRI marked contrast enhancement is found and the
which may occasionally contain myelinated nerve meningioma surface is often nodular, what is depicted
fibers. Most of them are less than 1.5 cm and are in the Fig. 6. On MRI sometimes the point of origin
found in the posterior hypothalamus (Fig. 5C and D). may be located, which can contribute to distinguish
They occur more often before two years of age and pituitary adenoma. In some cases copious meningi-
express gonadotropin-releasing hormone (GnRH), oma vascularization may give rise to a blush on digital
releasing such hormone in a pulsatile manner, leading cerebral angiography.
480 Part V / Neuroendocrinology

Fig. 5. Four-year-old boy with precocious puberty harboring hypothalamic hamartoma. Coronal (A) and sagital (B) views.
Note the similarity of TI weighted features between the mass and brain.

Surgery, preferably through a transcranial approach, tricle more frequently present neurological and
is the treatment of choice; as such tumors are firm opthalmological disturbances, but other important
and highly vascularized, a trans sphenoidal approach neurological findings are cerebellar abnormalities and
would compel the surgeon to proceed, in the majority mental changes. Endocrine abnormalities are not fre-
of cases, through a normal pituitary gland, entailing quent.
further hormonal impairment. The best therapeutic choice for such tumors is con-
troversial. Some authors advocate medical follow-up
2.5. Glioma alone, because of benign course of such lesions, unless
Optic and hypothalamic glioma accounts for 1-3% they cause neurological deficits. Others defend a con-
of brain tumors in children and adolescents. The three ventional or stereotaxic radiation therapy, which
types of astrocyte-derived neoplasms, astrocytomas, would lead to growth inhibition or delayed tumor
anaplastic astrocytomas, and glioblastomas, can be recurrence.
found in the hypothalamus. Most typical is the pilo-
cytic astrocytoma, arising on the third ventricle walls 2.6. Chordoma
or optic paths in 75% of cases. The remaining 25% Chordomas are rare, locally invasive tumors, aris-
are intraorbital. Two types of pilocytic astrocytomas, ing from intrabony notochord remnants. They are
adult and juvenile, are found. The former is usually slow growing tumors and metastasis rarely occurs.
firm and, although not reaching a large size, tends to Chordomas occur more often in the sacral-coccygeal
be more invasive and aggressive than the latter. The region and about one third in the clivus (at sphenoid-
juvenile type occurs before the age of two in about occipital synchondrosis). On imaging assessment,
40% of cases, and in 80% before ten years of age. osteolytic bony erosion and occasional calcification
About 20-33 percent of bearers of optic gliomas have are found. Surgery has been the exclusive treatment,
neurofibromatosis. Gliomas of the posterior third ven- recurrence is the rule, with an average 5-yr survival.
Chapter 27 / Hypothalamic Disease 481

Fig. 7. CT scan coronal view of an expansive macroprolacti-

noma leading to intracranial hypertension (note the dilated
lateral ventricules).

Cushing's disease, are most often microadenomas and

even in its macroadenoma presentation rarely expand
to the hypothalamus. Nevertheless, in the case of
Cushing's disease treated by bilateral adrenalectomy,
the ACTH-producing adenoma may become more
aggressive and expansive producing what is known
as Nelson's syndrome.
At clinical presentation, patients with expansive
adenomas usually have visual disturbances due to
optic chiasm compression. Headache owing to menin-
geal expansion and symptoms related to the compres-
sion of cranial nerves, should the cavernous sinus be
affected, can also occur. The association of hydro-
cephalus with pituitary adenomas is rare but can be
present in cases of large suprasellar expansion
Fig. 6. Coronal view of MRI (Tl weighted) of a meningioma
arising from the tuberculum sella. (Fig. 7). In addition to the neuroophthalmologic
symptoms, further symptoms can be found depending
on hormonal hypersecretion (hyperprolactinemic syn-
This kind of tumor is frequently resistant to adjunctive drome, giganto-acromegaly, Cushing's disease, or
therapy as chemotherapy or radiotherapy and rarely Nelson's syndrome) or hyposecretion (hypopituita-
do they develop into sarcomatous tumors, with an rism owing to destruction or compression of the nor-
aggressive natural history. mal pituitary gland, hypothalamic nuclei responsible
for pituitary function control, or pituitary stalk). The
2.7. Pituitary Tumors association of diabetes insipidus with nontreated pitu-
Pituitary adenomas account for 10% of brain tumors. itary adenoma is rare, and more common after surgi-
According to their size, such tumors can be classified cal treatment.
into microadenomas and macroadenomas. Macroade- The tumor is diagnosed and located with the aid
nomas can be expansive and invasive (Fig. 7), leading of imaging methods, the most accurate of which is
to hypothalamus compression and dysfunction. Pitu- MRI. Such examination shows the tumor location and
itary carcinomas are exceedingly rare. size, as well as its relation to adjacent structures as
Prolactinomas are the most frequent pituitary ade- the optic chiasm, cavernous sinus, sphenoidal sinus,
nomas, followed by "clinically nonfunctioning" and and hypothalamus. Cystic or hemorrhagic compo-
GH-producing adenomas. Apart from being rarer, nents of the tumor can also be depicted. CT is also
ACTH-producing adenomas, which account for useful, particularly in identifying calcifications and
482 Part V / Neuroendocrinology

Fig. 8. MRI (T I weighted coronal

views) of an acromegalic patient:
(A) before and (B) after transsphenoi-
dal surgery. Note the complete removal
of tumor mass.

the integrity or damage of bone structures, such as the extension of the tumor, is indicated. Compressive
the sellar floor. symptoms almost invariably improve following such
Hormonal assessment is necessary to determine treatment. Complete tumor resection will depend on
hormone hypersecretion and status of the pituitary the surgeon expertise and adjacent structures invasion.
function. Prolactinoma diagnosis is given by high In functioning adenomas, persistence of hormonal
serum prolactin levels, almost invariably higher than hypersecretion reveals incomplete tumor resection
100 ng/mL. Lower levels can be related to clinically and further need of adjunct therapy. In clinically non-
nonfunctioning tumors, which lead to hyperprolactin- functioning adenomas, MRI after surgery will show
emia by pituitary stalk compression, hindering the the presence of tumor remnants. In the case of incom-
dopamine flow to the normal pituitary gland. Hyper- plete tumor resection, irradiation has been the most
prolactinemia can also occur in association with used treatment. In acromegaly, the use of somatostatin
growth hormone production in cases of acromegaly. analogs may lead not only to reduction or normaliza-
Glycoproteic hormone-producing tumors (LH, FSH, tion of GH and IGF-I, but also to tumor reduction;
and TSH) are rare and can lead to hypersecretion therefore, such agents can be used as primary treat-
syndrome, as, for instance, hyperthyroidism. Acro- ment in patients when surgery is contraindicated or
megaly diagnosis (GH-producing tumors) is estab- following partial surgical resection, either associated
lished by the finding of high levels of serum GH or not with radiation therapy.
(basal or during GTT) and IGF-I, inadequate to the Surgery will allow the histological diagnosis, and,
patient's sex and age. In the case of Cushing's disease by means of immunohistochemistry or in situ hybrid-
associated with pituitary microadenoma, laboratory ization, the functional diagnosis of the tumor. Clini-
diagnosis is usually aided by tests of ACTH/cortisol cally nonfunctioning adenomas may express hor-
suppression or stimulation, and in unclear cases, mones, mainly gonadotropins.
petrous sinus catheterization can confirm pituitary Hypopituitarism treatment, of both pituitary and
ACTH production. In Nelson's disease, the clinical hypothalamus origin, should be carried out with
assumption is confirmed by high ACTH serum levels. proper hormonal replacement, as dealt with in a fur-
Assessment of patients with expansive pituitary ther chapter.
tumors includes a thorough ophthalmic examination
with evaluation of visual fields. 2.8. Metastatic Tumors
The treatment of choice for pituitary adenomas is Metastases to the hypothalamus-pituitary region
almost invariably surgical (Fig. 8), except for prolacti- occur in approximately 3.5% of cancer patients. The
nomas. Such cases are initially treated with dopamin- posterior pituitary gland is the prevalent location for
ergic agonists, which may lead to normalization of such metastases, probably because of their systemic
prolactinemia, tumor regression (Fig. 9), and recovery circulation-dependent irrigation. Diabetes insipidus is
of the visual and neurological condition, depending the first manifestation in 70% of cases. Malignant
on tumor expansion. Surgery for this type of tumor tumors that mostly metastasize to this region are:
is indicated only for cases that do not respond to breast (47%), lung (19%), gastrointestinal tract (6%),
clinical treatment. For other adenoma types, surgery, and prostate (6%) tumors. Figure 10 shows the CT of
either transsphenoidal or transcranial, depending on a patient with breast cancer and sellar and suprasellar
Chapter 27 / Hypothalamic Disease 483

Fig. 9. Macroprolactinoma treated by bromo-

criptine. Coronal view of MRI (Tl weight-
ed). (A) Before treatment: showing an huge
invasive macroprolactinoma with suprasellar
and parasellar extensions and sphenoid
sinus invasion. (B) During treatment: note
near complete disappearance of tumor mass
with secondary empty sella.

Fig. 10. CT scan coronal view of a breast

metastatic tumor to the sellar region in a
42-year-old female patient.

metastases. Up to 25 % of women with metastatic 2.10. Granulomatous/lnflamatory Diseases

breast cancer have pituitary metastasis. Sometimes
pituitary adenomas cannot be distinguished by means 2.10.1. SARCOIDOSIS
of the available imaging methods, but in other occa- Idiopathic granulomatous disease, which may
sions bone destruction draws attention to the diagnosis affect almost any organ. About 5% of cases involve
of metastasis. the nervous system, 1.35% involve the central nervous
system (eNS), and 0.53%, the hypothalamus-pitu-
2.9. Dermoid and Epidermoid Tumors itary region, ranging from a mere meningeal thicken-
Dermoid and epidermoid tumors are rare tumors, ing to actual circumscribed masses. The disease
resulting from inclusion of epithelial elements at the courses subacutelly or chronically, mimicking other
time of neural tube closure. The epidermoid tumors granulomatous lesions or neoplasms There is no gen-
are more common and contain a pearly fluid. The der predominance and hilar adenopathy occurs in 66%
dermoid type contains dermic appendices such as hair of cases on chest roentgenogram; it may present with
follicles and sebaceous or sweat glands. Surgery is lytic lesions of the skull . Diabetes insipidus (37.5%)
the treatment of choice. and cranial nerves palsy are common findings and,
484 Part V / Neuroendocrinology

sometimes, dysthermias, somnolence, hypodipsia, niazid, rifampin, and a third drug, which may be
and obesity may also occur. Hypothalamic hypopitu- ethambutal or pyrazinamide. Under the influence of
itarism is frequent. Cerebrospinal fluid shows a slight these drugs, the tuberculoma may decrease in size
lymphocitic pleocytosis and moderate increase in pro- and ultimately disappear; otherwise, excision may
tein content and gamma globulin. The glucose content be necessary.
is reduced in some patients. Sarcoid granulomas must
be searched by biopsy in other tissues (uveal tract, 2.11. Radiation-Induced Lesions
skin, lungs, and bones). Some of the deficits improve In the short term, brain irradiation may lead to
with glucocorticoids. Prednisone, in daily doses of vomiting, drowsiness, and focal motor signs. Later
40 mg is given for 2 wk, followed by 2-wk periods lesions occur more often 1-3 yr following applica-
in which the dose is reduced until a maintenance dose tions, sometimes appearing much later. Intellectual
from 10 to 20 mg is reached. Therapy should be deterioration, leukoencephalopathy, and endocrinop-
continued for at least 6 mo, and in many cases for athy are included. The pituitary, as compared to the
several years. hypothalamic tissue, is more radiation-resistant. Brain
irradiation before two years of age almost invariably
2.10.2. HISTIOCYTOSIS X leads to endocrinopathies, which are less common
Term referring to a group of histiocytic alter- when the procedure is carried out after 11 yr of age.
ations, ranging from bone eosinophilic granuloma Adults are less likely to develop hypopituitarism after
to disseminated, generally lethal, disease of soft radiation therapy as compared to children and adoles-
tissues. Sometimes the course is that of an inflam- cents. Hypothalamic injury is proportional to the radi-
matory disease, others that of a neoplastic one. In ation dose used, and complications are reduced with
Hand-SchUller-Christian disease multifocal eosino- greater fractionation of the total dose; endocrine insuf-
philic granulomas occur, often affecting the skull. ficiency is time-dependent.
It is the mostly involved condition considering Radiation-induced tumors, mainly of the malignant
hypothalamus-pituitary located lesions, and leads to glioma type, although rare, are often fatal.
the triad exophthalmos, lytic lesions in membranous
bones, and diabetes insipidus, the latter occurring 2.12. Traumatic Lesions
in about one third of patients. Some cases are The hypothalamus is a region vulnerable to lesions
associated with the presence of hypothalamic anti- secondary to severe brain trauma. Necropsy studies
bodies, probably as a result of hypothalamic lesion; in subjects who underwent fatal brain trauma have
hypopituitarism and hypodipsia are also found. shown lesions of the posterior pituitary gland, pitu-
Additionally, we can find enlarged lymph nodes, itary stalk, and anterior pituitary gland, as well as
spleen, or liver. Biopsy for any suspecious lesion, capsular bleeding. Both microscopic and macroscopic
specially in the skin must be performed. The assess- hypothalamic hemorrhage were found in 42% of the
ment should be repeated 1-2 times annually if examined corpses. The typical hypothalamic trauma
negative. Low-dosing radiation therapy, corticother- patient is young, male, victim of a car accident, whose
apy, and chemotherapy have been used with disease first shock organ is the head. Such patients usually
control, however, often with no regression of either suffer a frontal, temporal, or skull base fracture, and
diabetes insipidus or hypopituitarism. show clinical evidence of lesion of the second, third,
fourth, and sixth cranial nerves, with a frequently
2.10.3. TUBERCULOSIS
prolonged coma. Diabetes insipidus may be associ-
Hypothalamic tuberculomas are tumor-like masses ated with the clinical setting in the acute phase. Ante-
of tuberculous granulation tissue that may produce rior pituitary hormonal deficits may appear some
symptoms of a space-occupying lesion. It rarely weeks or months following trauma and are often
occurs in the majority of the countries, but in some underdiagnosed. In the acute phase of prolonged
underdeveloped countries they constitute from 5 to coma, dysthermias and hemodynamic instability
30% of all intracranial mass lesions. Because of their occur more often, frequently aggravated by dehydra-
proximity to the meninges, the spinal fluid often con- tion resulting from polyuria, increase in insensitive
tains a small number of lymphocytes and increased losses because of hyperthermia or even an adrenal
protein, but the glucose level is often normal, unlikely failure secondary to damaged CRH production cells.
of tuberculous meningitis, which presents with In case of hypotension, corticosteroid agents should
reduced spinal fluid glucose. Treatment includes iso- always be administered. Hormonal deficit, which may
Chapter 27 / Hypothalamic Disease 485

occur in hypothalamic trauma, as a rule follows the from daily up to a decade-interval. The onset is abrupt
usual sequence of events, the somatotrophic sector with no triggering event or environmental change.
being most commonly affected, followed by the Duration ranges from minutes to days, and body tem-
gonadotrophic, thyrotrophic, lactotrophic sectors, perature may fall to 32°C or lower. Tearing, asterixis,
and, finally, the corti co trophic axis. Precocious ataxias, cardiac arrhythmias, arterial hypotension,
puberty secondary to hypothalamic trauma has been hypoventilation, and loss of consciousness can occur.
described and may distort a GH-deficit condition in The model is that of a lower set-point. Hypothermia
childhood. has been associated to third ventricle steatoma, glio-
sis, and cellular loss in the premamillary and arcuate
3. HYPOTHALAMIC SYNDROMES nucleus regions, and corpus callosum agenesis.
Although several features of paroxysmal hypother-
3.1. Dysthermias mia suggest an epileptic crisis modifying the hypo-
thalamus thermostat, most patients fail to respond to
3.1.1. HYPERTHERMIA anticonvulsants.
Acute lesions of the anterior hypothalamus and
preoptic region may result in an up to 41°C (lOS.SOP) 3.1.3. POIKILOTHERMIA

temperature rise, tachycardia and loss of conscious- Poikilothermia is defined as a body temperature
ness, usually for less than 2 wk. The mechanisms of oscillation of at least 2°C on account of environmental
heat production are maintained, whereas those of heat temperature changes. In this dysthermia, found most
dispersion show failure. A clinical clue to differentiate frequently in humans, mechanisms of both heat pro-
infectious fever from inflammatory fever is a less duction and heat dissipation are damaged. Its severity
accelerated heart rate in the hypothalamic hyperther- varies, according to the type and degree of the hypo-
mia. In case of highly elevated hyperthermia, we thalamus lesion.
should consider the malignant neuroleptic syndrome, Poikilothermia results from destruction of posterior
more related to drugs of higher antidopaminergic hypothalamus or rostral midbrain. Hypothalamic
potency. Muscle contractions occur and may lead to lesion should be bilateral in order to poikilothermia
rabdomyolisis, and as a result, high serum CPK levels to occur. Many patients fail to realize their condition
and renal failure. A possible aggravating factor of and show no signs of discomfort. As room tempera-
this syndrome is the inhibition of sweating, owing to ture is usually lower than normal body temperature,
anticholinergic effects of neuroleptics. The con- patients are hypothermic most times, and only chil-
science level ranges from agitation and stupor to dren (of a higher metabolism) are rarely hyperthermic
coma. It lasts from S to 10 d, killing 20-30% of the in warm environments.
affected patients.
Chronic hyperthermia develops in lesions of the
3.2. Feeding Disorders
tuberal-infundibulum region. They may result from
loss of heat dispersion mechanisms, stimulation of the Human beings maintain the same body weight for
maintaining mechanisms, or increase in the activation years. Should a small caloric gain or loss occur daily,
threshold of dispersion mechanisms. The general in a very short time, we would have deep weight
health status is often maintained and long-term hyper- variations. Somehow, signs that modulate either food
thermia occurred in 10% of Bauer's cases. It may intake or metabolism are sent, however, there is a
respond to sedative or anticonvulsive agents, but not difference between food intake and temperature regu-
to salicylates. lation. Temperature is very similar among individuals,
whereas body weight is quite different and is, to a
3.1.2. HYPOTHERMIA
larger extent, influenced by other factors such as
Hypothermia can occur in either a continuous or stress, food appreciation, exercise and several other
a paroxysmal way. The condition results from injury environmental and genetic factors. The control of
to heat-producing mechanisms or establishment of a food intake might act not as a single set-point, but
newer, lower set-point. The continuous form is rare as several set-points coexisting. Such control can be
and may be because of anterior hypothalamus injuries. helped by the fat storage mechanism, in which the
Patients usually maintain the heat dissipation mecha- larger the amount of nutrient intake, the lower the
nisms. In paroxysmal cases, crisis of a fall in body food conversion into fat, maintaining a stable storage
temperature may occur, whose frequency may range even with a nutrient intake variation. However, if
486 Part V / Neuroendocrinology

such intake is persistently high, the mentioned set- infiltration. Hyperphagia and obesity are also associ-
point may rise. ated with syndromes as Laurence-Moon-Bardet-
Caloric expenditure also tends to be quite stable, Biedl and Prader-Willi.
as shown in studies of animals on ad libitum diet. The As already mentioned regarding hyperthermia,
animals may gain weight when feeding is imposed or hypothalamic hyperphagia is followed by other symp-
when extremely tasty food is provided, and they may toms related to disorders of this region, such as diabe-
loose weight if calories are limited. Under such condi- tes insipidus, drowsiness, convulsions, hypodipsia,
tions, the relation between energetic expenditure and and anterior pituitary hypofunction. Antisocial behav-
body weight changes: slim animals require fewer cal- ior and improper aggression are usually shown in
ories to keep their weight and the opposite occurs hypothalamic obesity.
with the heavier ones. In some cases, the satiety set-point seems to be
Food intake seems to be controlled by two hypo- reset. This occurs more often following head injury,
thalamic nuclei: ventromedial nucleus, whose de- and an exaggerated gain in body weight occurs in the
struction leads to hyperphagia, and lateral hypothala- first six months, with a trend towards late stabilization
mus, which causes aphagia when destroyed. Based and, sometimes, loss of weight, reaproaching pre-
on such findings, the former is believed to be the trauma level. The syndrome can also result from
nucleus of satiety and the latter, the nucleus of hunger. tumors in the region, which, when enlarged, may
There are, however, controversies as to the existence worsen a preexistent hyperphagia. What establishes
of simple nuclei controlling specific functions in the the new set-point remains unexplained. When one
hypothalamus. encounters a patient with hypothalamic obesity, the
Several humoral signs such as blood glucemic lev- presence or absence of hyperphagia at that particular
els, insulin, glucagon, serotonin, cholecystokinin, point in time depends on whether or not the subject
neuropeptide Y, and leptin, seem important in the has attained his new set-point body weight. Some
regulation of the feeding behavior, and are discussed authors have commented on a tendency toward cen-
further in this book. tripetal fat accumulation with true hypothalamic obe-
Although the compUlsive eater stands for an sity. These patients have a more severe hyperinsuli-
acknowledged clinical disorder, actual hyperphagia nemia when compared to the exogenous obese of
has been well documented in hypothalamic lesions. same weight, probably a result of vagus liberation,
already documented in animals with ventromedial
3.2.1. HVPERPHAGIA AND OBESITV
nucleus injury.
Mohr in 1840 first described hypothalamic lesions
causing obesity and Hogner further localized the criti- 3.2.2. HVPOTHALAMIC CACHEXIA

cal zone to the basal hypothalamus. Hyperphagia and Only few adults have shown the aSSOCIatIOn of
obesity affect 25% of patients with hypothalamic dis- cachexia with other hypothalamic symptoms. Kamal-
ease, although rarely as initial manifestations of hypo- ian described a woman who had a progressive wasting
thalamic dysfunction. Reeves and Plum described a illness accompanied by hypophagia, but in spite of
young woman who developed marked hyperphagia high-caloric tube feedings she continued to lose
and obesity associated with aggressive behavior pla- weight. At autopsy, the underlying illness of multiple
cated only by giving an 8000 kcal per day diet. At sclerosis had produced both new and old plaques
autopsy, she was found to have a hamartoma precisely involving the lateral hypothalamic regions. In Bauer's
and completely destroying the ventromedial hypothal- series, 18% of cases had significant weight loss, 8%
amus. A young man studied by Anderson was found bulimia, and 7% anorexia. The destruction of the
to have only partial ventromedial destruction because ventromedial nucleus and the lateral hypothalamus
of encephalitis, and he had developed mild obesity. leads to anorexia, which also occurs in isolated lateral
Apparently, the degree of ventromedial destruction hypothalamic lesions. Rapid weight loss, muscular
influences the degree of obesity in man and in animals. hypotrophy, activity reduction and hypophagia occur,
The bilateral destruction of ventromedial nuclei leading to cachexia and death; it is more often the
causes obesity both in human beings and in other result of neoplasms.
animals. Patients with such lesions usually have CNS
neoplasms, 60% of which being craniopharyngiomas. 3.2.3. KLEINE-LEVIN'S SVNDROME

Only 6% have inflammatory or granulomatous pro- Kleine-Levin's syndrome is most common in male
cesses, 5% posttrauma lesions, and 2% leukemic adolescents, and is characterized by repeated episodes
Chapter 27 / Hypothalamic Disease 487

of hypersomnia, hyperphagia, hiperactivity when dexamethasone suppression and hyporesponsiveness

awake, and behavioral disorders, particularly hyper- to CRH injection. These abnormalities found in the
sexuality. Compulsive eating is not necessarily linked dynamics of the hypothalamus-pituitary-adrenal axis
to bulimia. Crises last from days to weeks, and resolve are also found in patients with major depression and
with no sequelae. During the symptomatic period the whether such hypothalamic abnormalities reflect a
night sleep is of poor efficiency, sleep is fractionated hypothalamic etiology of the syndrome or whether
and 3, 4, and REM (rapid eye-movement) sleep stages these manifestations are mere epiphenomena of a pri-
are reduced. A 24-h hormonal sampling performed marily psychiatric syndrome remains to be deter-
every 20 min has shown elevation of TSH and prolac- mined.
tin mean values and reduction of GH and cortisol in The treatment of anorexia nervosa patients aims,
the symptomatic period, which strengthens the theory at first, at their renutrition, many times demanding
of dopaminergic tonus reduction in such patients. The hospitalization with enteral or even parenteral diet.
etiology is unknown, however, some patients have a An individual or group psychotherapy work is concur-
previous viral infection. The disease usually remits rently started, conducted by professionals having
in the third decade of life. expertise in such a disease. Medical treatment lies
basically in the use of antidepressive medications.
3.2.4. ANOREXIA NERVOSA

There is evidence supporting a hypothalamic dys- 3.3. Sleep Disorders

function component in this disorder. Patients may
present with hyperprolactinemia, poikilothermia, dia- 3.3.1. HYPERSOMNIA

betes insipidus, and hypothalamus-anterior pituitary Hypersomnia is the most common disorder, the
dysfunction described below. It most often affects prevalence in hypothalamic dysfunction being 30%.
middle or upper class young women, who have a In acute lesions, the most involved regions are peria-
distorted self-image, considering themselves as obese, queductal gray matter, mamillary bodies, and the acti-
and making exaggerated feeding restriction, many vator reticular system. When the posterior hypothala-
times associated with an intensification of physical mus is affected, hypothermia and irritability are
exercises. They commonly develop a bulimic behav- associated. The most common causes of hypersomnia
ior, vomiting after meals; other times, they take diuret- are neoplasias, mainly craniopharyngioma and
ics or cathartic agents on their own. germ cell tumors and about 40% of patients are
The endocrine abnormalities are diverse, with also obese.
amenorrhea as major prevalence, sometimes preced-
3.3.2. INSOMNIA
ing weight loss, and persisting even after the reestab-
lishment of normal weight. Gonadotropins are hypo- Insomnia may occasionally mean hypothalamic
secreted, both spontaneously and following GnRH lesion in the anterior and preoptic region and some-
stimulus. After weight reestablishment, the patients times (especially in hypothalamus cystic tumors) it
develop a "second puberty," with nocturnal LH pulses is accompanied by daytime sleepiness. Lesions of the
and reappearance of gonadotropin release to GnRH. tuberal region may have clinical presentation similar
The serum level of IGF-I is often low and the to akinetic mutism.
basal GH may be normal or high, as in the undernour-
ished. A paradoxical response to both glucose and 3.4. Behavioral Disorders
TRH may be present, with normal response to GHRH. Hypothalamus appears to affect behavior in three
Such abnormalities revert to normal with weight spheres: it coordinates the motor, autonomic, and
reestablishment. endocrine components of behavior; it produces the
As far as thyroid function is concerned, such behavior appropriate to the affective state; and it
patients behave as in the syndrome of euthyroid sick influences the intensity of each behavior. Behavior
disease, and the physician should be aware for the has a complex supra tentorial, limbic, and hypothala-
differential diagnosis with true hypothyroidism, mic regulation. The latter seems to integrate the appro-
because thyroid reposition in anorectic patients is not priate emotional expression. Aggressiveness, emo-
recommended. tional lability, and destructive antisocial behavior
There is evidence supporting a reduced cortisol form a spectrum of emotional disorders involved in
clearance, with high serum levels leading to low ventromedial nucleus lesion. Although there are
ACTH levels. There may be no response to I mg reports of hypersexual behavior with compulsive
488 Part V / Neuroendocrinology

masturbation, hyperphagia and hallucinations, most mus or optic paths. Children seem normal at birth,
sexual dysfunctions of hypothalamic origin are of the but at the end of their first year, they start losing
hypogonadic type. The already described Klein- weight and showing hyperactivity signs, with no
Levin syndrome, of which etiology is speculated to be growth impairment. They seem to be always alert
a hypothalamic functional abnormality, affects mostly because of eyelid retraction. Although appetite is
male adolescents with recurrent episodes of hyper- maintained, nystagmus, vomiting, tremors, and optic
somnia, annoyed wakenings, incoherent speech, hal- atrophy may evolve. The night-day cortisol cycle is
lucinations, forgetfulness, masturbation, and compul- lost and a paradoxical GH response to glucose load
sive eating. These symptoms are accompanied by a may develop, as well as high basal levels. The children
feeling of indolence and headache. The episodes occur usually die before two years of age, but those who
at intervals of 3-6 mo and last for 5-7 d, sometimes survive longer maintain appetite, gain weight and
even for weeks. Spontaneous cure occurs quite often become obese. The pleasant personality is gradually
at late adolescence or early adult life. replaced with irritability and drowsiness and preco-
cious puberty may develop.
3.5. Diencephalic Epilepsy
Convulsion hypothalamic etiologies are rare. Sei- 3.B. Diencephalic Glucosuria
zures include coordinated patterns of intense auto- Hyperglycemia and glucosuria may follow hypo-
nomic hyperactivity. During a typical crisis, the child thalamic lesions in the tuberal-infundibular region,
stops his/her activities, starts laughing, groaning, and mostly reported following basal skull fractures, intra-
presents uni- or bilateral clonic movements of the cerebral hemorrhages, or surgeries involving the third
ocular, eyelid, or mouth muscles. Consciousness is ventricle floor. In patients with skull trauma, high-
maintained, unless the crisis is followed by a major glucose levels are a relatively common finding, sec-
or petit mal convulsion. Gelasmus or laughter crises ondary to factors leading mainly to insulin resistance,
may be found in patients with tuberal hamartomas. such as stress, infections, dexamethasone use, infu-
These hamartomas, if totally excised, may be fol- sion of rich glucose parenteral solutions. However,
lowed by complete control of the crisis. Partial exci- lesions in the above mentioned regions seem to pose
sions usually fail to lead to the same result. a greater risk to hyperglycemia development.
3.6. Authonomic Dysfunction 3.9. Thirst and ADH Secretion Disorders
Stimulus of the suprasympathetic region in the The control of plasmatic osmolality and its major
anterior preoptic hypothalamus leads to a vagus determinant, plasma sodium, results mainly from
response with miosis, hypotension, and bradycardia, mechanisms of water conservation, mediated by
and an increase in the visceral blood flow to the ADH, and from thirst-induced water ingestion. There-
disadvantage of a lower muscular blood flow. Yet, fore, disorders that affect fluid balance are the main
when the postero-medial hypothalamus, area of the responsible for alterations of plasmatic osmolality and
sympathetic nervous system, is stimulated, a typical cause hyper- or hypotonic syndromes. The clinical
fight and flight reaction occurs with mydriasis, tachy- manifestations of these disorders are consequences
cardia, and tachypnea, and an increase in arterial ten- of alterations of cellular volume, particularly at the
sion, hair erection, and visceral blood flow reduction CNS level and of effective circulating volume.
and muscle blood flow increase, as if preparing the
subject to fight or flight. 3.9.1. ESSENTIAL HVPERNATREMIA

The autonomic dysfunction secondary to hypothal- AND ADIPSIC HVPERNATREMIA

amic lesions may lead to symptoms such as lower Hypernatremia in adults rarely occurs because of
threshold to cardiac arrhythmia, arterial hypertension, excessive sodium ingestion. By and large it is second-
gastric and duodenal erosions and hemorrhages (there ary to a deficiency in water ingestion. In the absence
are reports of gastric acidity and pepsin increase in of major liquid losses, chronic hypernatremia in con-
anteromedial hypothalamus lesions) and, rarely, acute scious individuals with free access to water is a result
pulmonary edema. of inappropriate lack of thirst.
Essential hypernatremia is secondary to thirst
3.7. Diencephalic Syndrome of Childhood decrease associated to a readjustment towards higher
Described by Russell in 1951, this syndrome occurs osmotic threshold. Therefore, these patients are able
in about 80% of low-grade gliomas of the hypothala- to concentrate and dilute urine at an osmolal level
Chapter 27 / Hypothalamic Disease 489

higher than that usually observed, and unlike patients ence of ADH-secreting antineuron antibodies is
suffering from adipsic hypematremia, they are pro- observed in approximately one-third of these patients.
tected from extreme hypematremia because they Brain lesions resulting from accidents or neurosur-
maintain some degree of osmoregulation. gical procedures are the most common cause of cen-
In adipsic hypematremia syndrome, thirst defi- tral DI. Some statistics have shown central DI as a
ciency is caused by alterations of osmoreceptors and complication of up to 75% of suprasellar surgeries
it is commonly associated to defects in the osmotically for removal of craniopharyngiomas in children. In
regulated ADH secretion. These patients present adults the incidence is lower. DI occurrence after
secretion of a small amount of ADH not related to trans sphenoidal surgery is approximately 10-20%.
plasmatic osmolality and may be exposed to both Persistent DI develops only after a sufficiently high
hypo- and hypematremia. lesion in the supra-optico-hypophyseal tract, causing
bilateral neuronal degeneration of supra-optic and
3.9.2. DIABETES INSIPIDUS (01)
paraventricular nuclei. In surgeries of the pituitary
The deficiency of ADH secretion or of its renal fossa, transitory DI may occur. Postoperative DI may
action leads to decreased urinary concentration ability present a three-phase course: (a) acute phase: charac-
and excessive excretion of urine. The resulting syn- terized by polyuria right after surgery, persisting for
drome, manifested by polyuria and polydipsia, is four to five days; (b) interphase: characterized by
known as Diabetes Insipidus and may have different regression of polyuria as a result of an autonomous
etiologies as shown on Table 4. release of ADH by degenerated neurons, and lasts for
3.9.2.1. Etiologies: Central Diabetes Insipidus. 5-7 d; and (c) permanent DI: polyuria is definitively
Known as neurogenic, cranial, or hypothalamohypo- established. It is important to recognize these three
physeal DI, it is manifested only when there is phases in order to prevent fluid intoxication that may
involvement of at least 80% of ADH-secreting hypo- occur during interphase if hypotonic fluid infusion,
thalamic neurons. The removal of the neurohypophy- initiated in the acute phase, continues.
sis may not result in DI, because proper amounts of Several lesions in the hypothalamohypophyseal
ADH may be released to systemic circulation from region are concurrent with central DI and must be
the stump of the hypophyseal stem. This explains investigated by means of neuroophtalmologic and
why tumors in the anterior pituitary compressing the neuroradiologic diagnostic procedures (Table 4). DI
neurohypophysis are rarely concurrent with DI. seldom occurs during normal pregnancy, secondary
The hypothalamic involvement in DI accounts for to a placental production of vasopressinase. Polyuria
the largest number of cases. The estimated incidence generally starts in the third quarter and spontaneously
of central DI is 1:25,000 cases, and occurs equally disappears in the immediate puerperal period.
in both sexes.
3.9.2.2. Nephrogenic Diabetes Insipidus. Nephro-
Familial neurohypophyseal DI is a rare autosomal
genic DI is secondary to hyporesponsiveness of the
dominant disorder, linked to AVP-neurophysin gene
renal tubular cells to ADH action, resulting in renal
mutations. Symptoms appear at birth or some years
excretion of persistently hypotonic urine in the pres-
later and circulating ADH levels may temporarily
ence of normal plasma or high ADH levels. It may
vary from undetectable to normal. Some cases of
result from different causes (Table 4).
sporadic congenital central DI have already been
described. 3.9.2.3. Primary Polydipsia. Excessive water in-
The association of central DI with Diabetes Melli- gestion with total body water expansion and hypos-
tus, optical atrophy, and neurological deafness molality is the first event in primary polydipsia. The
(DIDMOAD) is the clinical picture of the Wolfram resulting drop in ADH plasma concentration causes
syndrome, an autosomal recessive condition. urinary dilution and polyuria, thus protecting the indi-
The idiopathic central DI, which accounts for vidual from hyperhydration. Inappropriate thirst may
approximately 30% of the acquired central DI cases, occur because of a psychiatric disorder (psychogenic
has its onset in infancy. This diagnosis may be made DI) or to an abnormality in thirst mechanism (dipso-
after excluding organic lesions of the hypothalamohy- genic DI).
pophyseal region. Patients suspected to have this diag- In psychogenic DI, water ingestion may start sud-
nosis must be periodically followed-up in order to denly and tends to fluctuate from one day to another.
detect intracranial lesions that may appear many years Dipsogenic DI may occur secondary to diseases
after the onset of the clinical picture of DI. The pres- involving the eNS, at hypothalamus level, such as
490 Part V / Neuroendocrinology

Table 4
Etiology of Diabetes Insipidus
Central
Congenital
Autosomal dominant
Autosomal recessive (Wolfram syndrome)
Sporadic congenital DI
Acquired
Head trauma
Postoperative
Associated to injuries in the hypothalamohypophyseal region
Primary tumors: suprasellar cysts, craniopharyngiomas, astrocytomas, germinomas, meningiomas, hamartomas,
hypophyseal adenomas, tumors of the hypophyseal stem, suprasellar tumors, gliomas
Metastatic tumors: lungs, breasts, leukemia and lymphomas
Granulomatosis: sarcoidosis, histiocytosis X, Wegener's granulomatosis, tuberculosis, syphilis
Vascular: sickle cell disease, cerebral aneurysm, vasculitis, cerebral trombosis or hemorrhage, Sheehan's
syndrome
Other lesions: empty-sella syndrome, intracranial hypertension and infections
Pregnancy (transient)
Idiopathic
Nephrogenic
Familial
Acquired
Renal diseases: chronic renal failure, polycystic disease, acute tubular necrosis, after obstructive uropathy, post
transplantation, chronic pyelonephritis, amyloidosis.
Systemic diseases with renal involvement: multiple myeloma, sickle cell anemia, sarcoidosis, Sjogren's syndrome,
Fanconi's syndrome
Metabolic: hypocalemia and hypercalcemia
Drugs: lithium, demeclocycline, alcohol, amphotericin, glyburide, glibenclamide
Primary polydipsia
Psychogenic
Dipsogenic

sarcoidosis, tuberculosis, vasculites, and tumors, or action in the kidney, to a maximum of 18 L, in absolute
it can be an idiopathic defect associated or not to ADH deficiency or ADH complete resistance condi-
abnormalities of ADH osmoregulation. A possible tions. Nycturia is almost always present. The symp-
explanation for dipsogenic DI is the lowering of thirst toms of hypertonic dehydration, irritability, mental
threshold. Therefore, thirst remains responsive to confusion progressing or not to coma, hyperthermia,
osmotic influences, but it occurs in plasmatic osmolal- and hypotension occur if access to water is not
ities lower than those that usually trigger thirst in ensured, such as in the cases of hypodipsia because
normal individuals. of impairment of thirst osmoregulation or in cases of
unconsciousness.
3.9.3. CLINICAL PICTURE Most of central DI cases present polyuria of acute
3.9.3.1. Central and Nephrogenic Diabetes Insip- onset; on the contrary, polyuria secondary to alter-
idus. The primary symptom of DI is persistent poly- ations of the renal mechanism of urine concentration
uria (24-h diuresis higher than 30 mL/kg), and urine is insidiously established. The major dilation of the
is hyposmolal in relation to plasma (uOsm lower than urinary tract may progress to hydroureter and hydro-
300 mOsm/kg or urinary density lower than 1010). nephrosis in patients with DI with onset in childhood.
The excreted volume of urine in a 24-h period may Finally, primary neurological symptoms in individu-
vary from few liters, in the cases of partial deficiency als with DI because of intracranial lesions may be
in ADH secretion or incomplete resistance to ADH prominent.
Chapter 27 / Hypothalamic Disease 491

3.9.3.2. Primary Polydipsia. The primary symp- 3-5% of body weight, 5U of aqueous pitressine or
tom is polydipsia together with polyuria. The polydip- 1 )lg of desmopressine (dDA VP) is administered by
sia of psychogenic etiology may be episodic. Diuresis SC or IV route when the patient has already emptied
may exceed 18 L in a 24-h period and nycturia is all bladder content. Sixty minutes later another sample
almost never present. must be collected to determine uOsm. This test must
be interpreted as follows.
3.9.4. DIFFERENTIAL DIAGNOSIS OF POLYURIA
In normal individuals fluid deprivation results in
DI must be differentiated from diabetes mellitus uOsm 2-4 times greater than pOsm and the subse-
and other forms of diuresis due to excess of solute. quent exogenous administration of ADH results in an
Hyperglycemia and glycosuria confirm the diagnosis increase lower than 9% in uOsm. Endogenous ADH
of diabetes mellitus. Clinical history is essential in levels are high and cause maximum antidiuresis.
order to identify other causes of diuresis due to excess Patients with primary polydipsia who present
of solute, as for example, recovery from acute renal medullar hypotonicity may discretely concentrate
failure, postobstructive diuresis or after solute admin- urine after water restriction. However, these patients
istration as sodium, mannitol, or contrasts. present maximum increase in endogenous ADH and
The differential diagnosis among the three types of an increase lower than 9% in uOsm after exogenous
DI is relatively simple when there is complete involve- ADH. Patients with primary polydipsia who decrease
ment. Thus, for example, a polyuria developed after their water ingestion and receive dDAVP some days
pituitary surgery and decreased with ADH administra- before the test may restore medullar hypertonicity
tion does not need further tests in order to confirm and present normal response.
the diagnosis of central DI. Nevertheless, the clinical Patients with complete central DI do not present
picture quite often does not help in the differential an increase in uOsm higher than pOsm during fluid
diagnosis because the syndrome occurs either with restriction, but they respond to exogenous ADH
incomplete abnormality or associated with diseases administration with an increase higher than 50% in
that may cause different subtypes of DI. For instance, uOsm. Those patients with partial central DI may
tuberculous meningitis may be associated with central present some degree of increase in uOsm during water
and dipsogenic DI, and sarcoidosis may cause the restriction, however increase of uOsm of at least 10%
three types of DI (central, nephrogenic, and dipso- after ADH administration is also observed.
genic). Some psychiatric patients presenting psycho- Finally, the water restriction test in individuals with
genic DI may be taking lithium or may have suffered complete nephrogenic DI does not cause an increase
cranioencephalic traumatism. In such cases, it is nec- in uOsm higher than pOsm, even after ADH adminis-
essary to use other criteria to establish DI diagnosis. tration. In the partial defect, exogenous ADH adminis-
Diagnostic evidence is based on renal capability tration results in some increase in uOsm.
to excrete hypertonic urine after osmotic stimulus. Many times water restriction test does not make
The simplest way to produce hypertonicity of body the discrimination of the three DI types possible,
fluids is fluid restriction. The absolute value of urinary because the percentages of uOsm increase after exog-
concentration obtained through this test depends on enous ADH administration may not differentiate pri-
the presence of ADH, and on the capability to stimu- mary polydipsia from partial defects of secretion or
late renal cells sensitive to ADH and on the hyperto- action of endogenous ADH.
nicity level of renal medula. DI diagnosis may also be established by means of
In patients with mild polyuria, water deprivation therapeutic test with A VP or its analogue dDAVP.
may start in the night before the test. However, in Thirst abolition, polydipsia, and polyuria triggered by
order to be observed, patients with severe polyuria administration of these compounds with no excessive
are submitted to water restriction only on the day of fluid retention suggest diagnosis of central DI. On
the test. During the assessment, fluid ingestion is the other hand, in nephrogenic DI, absence of effect
completely suspended and patients are prevented of these hormones in normal doses is observed. Nev-
from smoking. ertheless, therapeutic tests may bring some difficulties
Weight and vital signs (blood pressure and heart in its interpretation when some patients present aboli-
rate) are recorded every hour, and urine and blood tion of polyuria with delayed or not very potent effect
samples are collected to determine uOsm, pOsm, and over thirst and polydipsia. In these cases, there is
electrolytes. When two consecutive values of uOsm excessive fluid retention and development of hypona-
vary less than 30 mOsm/kg or when there is loss of tremia and hyposmolality.
492 Part V / Neuroendocrinology

15 •0
A
10

9
"
8 •
•
Plasma
Vasopressin
6
+
(pglmL)
• 0
+ 00

o 0+
0 0 0
o o~
lO
I 0
•••0 . ... . ••• _ . ,.
•
•

Du' lyd,a llon p.l rnS:'i.tl1

1200 +
~B
1000
+
+
~
0+
0

. •
600

~
0
Urine : 000 8
Osmolality 600
..
: !'"
•
0

...
(mOsm/kg)
8 •
•
: A. ..
300 : ' '0 •
~ 0 •
• • 0 •
• •
05 1 5 10 50 '50
Plas m a V asopressin
(pglmL)

Fig. 11. Diabetes insipidus. Relationship of plasma vasopres-

sin to plasma osmolality (A) or urine osmolality (B) during
fluid deprivation/hypertonic saline infusion in patients with
central (.A. or +), nephrogenic C-), or dipsogenic (0 ). (From
Robertson OL. Diabetes insipidus. In: Dluhy RO, ed. Clinical
Disorders of Fluid and Eletrolyte Metabolism: Endocrinology Fig. 12. A seven-year-old boy with central diabetes insipidus.
and Metabolism Clinics of No rth America, vol. 24. Philadel- (A) MRI coronal view (TI weighted) showing a thickened
phia, PA: W. B. Saunders, 1995 ; 3:566 [waiting for permis- stalk. (B) MRI sagital view (T I weighted) with disappearance
sion of W.B. Saunders Company].) of the typical posterior pituitary signal.

primary polydipsia or nephrogenic DI present ADH

The quantitative determination of plasmatic ADH release in response to hypertonicity. Patients with
concentration related to pOsm and uOsm may im- central DI do not release ADH or do it inappropriately.
prove accuracy of the differential diagnosis of the Recently, the urinary excretion of aquaporine 2 has
different types of DI (Fig. 11). Normal or high ADH been suggested as a tool for the differential diagnosis
concentrations in the presence of diluted urine suggest of DI. In central and nephrogenic DI, aquaporine 2
nephrogenic DI. Basal concentrations, below 1 pg/ excretion was shown to be low and increases after
mL impair the establishment of diagnosis and it is A VP administration, only in the former.
necessary to determine ADH during water restriction Another important tool in the differential diagnosis
test. In central DI, ADH is inappropriately low in of DI is the absence of the typical Tl weighted hyper-
relation to pOsm, whereas in primary polydipsia (as intensity of neurohypophisis in central DI (Fig. 12 B).
well as in nephrogenic DI) the ADH/pOsm ratio is
normal. The infusion of saline solution may be used 3.9.5. TREATMENT
in order to study ADH release in patients with no 3.9.5.1. Central DI with Preservation of Thirst and
limitations of cardiac reserve. This procedure consists Consciousness. When treating polyuria in these cases
of measuring pOsm and ADH plasmatic concentration our aim is to gi ve comfort to the patient, to improve his/
during infusion of hypertonic saline solution (3%), her life quality and to prevent urinary tract distention.
at 0.1 mLlkg/min, during two hours. Patients with Nontreated children may have sleep and feeding disor-
Chapter 27 I Hypothalamic Disease 493

ders that result in growth delay and learning problems. is to establish a strict control of fluid gains and losses,
Water must be always handy, however, the patient must because in DI the major loss is free water. The fluid
not be forced to drink if not thirsty. balance must be performed, including insensitive
The treatment of choice is desmopressin (dDAVP), losses and gain of endogenous water, based on the
a synthetic nonapeptide: 1-deamin-8-D-arginine vaso- last serum sodium level measured, which, if high,
pressin. There is much individual variation concern- indicates a need of water replacement by gavage or
ing required dosage and administration interval, as a glucose solution at 5%. In these cases, serum
which seems to be mostly independent on the size of sodium must be determined two or three times in 24 h.
the patient. The administration of dDAVP depends The treatment of patients with essential hypema-
basically on the measured 24-h urinary volume and tremia depends basically on an increase in fluid inges-
on the therapeutic regimen used. We should first pre- tion, but the control of patients with adipsic hyperna-
scribe the lowest possible dosage to make the patient tremia is extremely difficult. The administration of
slightly poly uric (2-2.5 Ll24 h), and to reduce the a set fluid ingestion results in wide fluctuations in
risk of water intoxication, especially in posttrauma plasmatic osmolality because of daily variations of
or postoperative DI, in which inappropriate secretion fluid losses. In these cases, fluids should be ingested
of ADH may follow DI within a few days. In adults, according to modifications in body weight. If ADH
this is easily obtained through nasal dosages of 2.5-5 secretion is insufficient, a fixed dosage of dDAVP
fJ,g (0.025-0.05 mL) every 12 h, or 0.1-0.2 mg of must be administered. Sodium and plasmatic osmolal-
oral preparation, twice or thrice a day. The maximum ity, if possible, must be regularly checked in order to
intranasal dosage should not exceed 40 fJ,g and in ensure not wide fluctuations in fluid balance.
children the initial nasal dosage depends on age: new-
borns: 0.25 fJ,g; infants: 0.5-1.0 fJ,g and children: 3.9.5.3. Inappropriate ADH Secretion. A pro-
2.5 fJ,g. If the first dosage does not produce a proper spective study demonstrated prevalence of hypona-
antidiuretic effect for at least 8 h, dosing will be tremia (serum sodium <130 mEq/L) up to 2.5% in
gradually increased. hospitalized patients. Hyponatremia is not only fre-
During follow-up, the need to increase dosage or quent, but also it is associated to a high level of
to shorten interval will depend on monitoring of 24-h morbidity and mortality when symptomatic. Some
diuresis. Side effects such as abdominal cramps, head- authors point out that such hyponatremia is because
ache and nasal congestion are rare. of an increase in total body water content, dependent
Although dDAVP is the drug of choice, there are on increase in fluid ingestion when ability to eliminate
alternative drugs in some cases mainly if 24-h diuresis water is reduced. The suppression of ADH secretion
is lower than 4-5 L. Three drugs have been used to avoids hyponatremia in normal subjects who ingest
increase ADH effect-chlorpropamide, carbamaze- up to 18 L of water within 24 h, and the kidneys
pine, and clofibrate. Chlorpropamide is the most effi- eliminate all exceeding water as maximally diluted
cient, alone or combined with dDAVP, in 125-500 urine. However, a syndrome of inappropriate secre-
mg dosage. Its major inconvenience is the risk of tion of ADH (SIADH) is characterized by maintained
hypoglycemia, especially if the patient suffers from ADH release usually not related to osmotic stimulus
hypopituitarism. Even if properly treated, the patient and fluid ingestion. The patient is either normal or
must remain under observation because hypoglyce- hypervolemic.
mia may occur again in the same day because of long Situations not defined as SIADH are related to
half-life of the drug, that is 36 h. Carbamazepine release of ADH by adequate nonosmotic stimulus,
may cause a severe adverse effect, aplastic anemia; such as in hypovolemia of adrenal failure and hypo-
however, if the patient needs an anticonvulsant in the thyroidism or in hypervolemia with damage to arterio-
postoperative period of a neurosurgery, carbamaze- lar filling in severe heart failure and cirrhosis. It is
pine must be considered. Clofibrate is usually not worthwhile to remember that these situations are fre-
very efficient. Other analog substances, such as pitres- quently associated with lower sodium supply to dilut-
sin and lysine-vasopressin, are no longer used because ing segments of Henle loop.
of side effects, half-life, and pain at administration. Such requirements may be found in hyponatremic
patients because of the use of certain drugs that may
3.9.5.2. DI with No Preservation of Thirst or Con- directly stimulate secretion of ADH or potentialize
sciousness. If the patient is confused, in coma, or its action in the collecting tubule, reSUlting in SIADH.
recovering from anesthesia, the main step to be taken This situation may occur during treatment with many
494 Part V / Neuroendocrinology

cytostatic, anesthetic, analgesic, and antidepressive 15

drugs and in the treatment of diabetes mellitus with (t 25.2)
chlorpropamide. Vincristin and cyclophosphamide
are drugs that may cause these side-effects, regardless
of nausea induced by them. Hyponatremia resulting
from diuretics may be a physiological response of
ADH secretion to hypovolemia.
3.9.6. PATHOPHYSIOLOGY

Administration of ADH, together with fluid inges-

tion with no restrictions, lead to hyponatremia, urinary
concentration, antidiuresis, and weight gain of about
3 kg. Approximately three days later, body weight
and sodium concentration are closer to a steady state 250 270 290 310
and natriuresis, the so-called sodium escape, occurs.
Plasma osmolality (mmol/kg)
High levels of natriuretic atrial peptide also contribute
to natriuresis. When fluid restriction is prescribed, Fig. 13. Patterns of ADH response to hypertonic saline solu-
hyponatremia is usually corrected, body weight is tion infusion in a group of hyponatremic patients with SIADH.
reduced and urinary sodium excretion is decreased, A = erratic release; B = readjusted osmostat; C = ADH leak-
even if ADH administration persists. Therefore, we age; D = normoregulated ADH (From Baylis PH. Vasopressin
may conclude that natriuresis, observed after three and its Neurophysin. In: DeGroot LJ, ed. Endocrinology, vol
1. Philadelphia, PA: W. B. Saunders, 1989:224 [waiting for
days of ADH administration, results from volume
permission of W.B. Saunders Company].)
expansion related to fluid retention, with reduction in
salt reabsorption in the proximal tubules. It is likely
that with the chronic use of ADH there is a partial osmostat to the left (type B). In these patients, ADH
escape in response to action of the drug. Because is responsive to modifications of plasmatic osmolal-
of sodium depletion, natriuresis lowers to sodium ity, but the threshold for ADH release and thirst is
ingestion level, and in this phase of SIADH urine may subnormal. These patients are able to perform osmo-
be poor in sodium. Because secretion of aldosterone regulation of water excretion retaining the ability to
is stimulated by hyponatremia, the secretion of this dilute and concentrate urine in an osmolality that is
mineralocorticoid may also contribute to reduce renal lower than normal. Because similar shifts to the left
loss of sodium in patients with hyponatremia and are observed in hypovolemia and hypotension, we
expanded volumes. Hyponatremic patients with suspect the cause may be a lesion in the afferent
SIADH present a disorder in thirst osmoregulation baroregulating paths. In some cases, ADH secretion
because they continue to present thirst at levels of cannot be entirely suppressed and the hormone
evident hyposmolality. There is also renal loss of "leaks" in low plasmatic osmolalities (type C). How-
substances such as uric acid, and its excretion varies ever, when plasmatic osmolality is increased, there
directly with effective circulating volume and with is a normal response of ADH release. The last group
sodium excretion rates. As a consequence, hypouri- (type D), represented by less than 10% of the patients,
cemia is frequent in SIADH. has completely normal osmoregulated secretion of
An investigation about osmoregulation of ADH ADH. Nevertheless, patients meet SIADH criteria
secretion in 25 patients, who satisfied the criteria because they fail to excrete a certain water load and
above mentioned concerning SIADH and presented are unable to maximally dilute urine. It is not known
several diseases, showed that there are four different whether this abnormality is because of increased renal
patterns of ADH release (Fig. 13). The first pattern sensitiveness to extremely low amounts of ADH or
(type A) is characterized by large fluctuations in plas- to other antidiuretic factor.
matic ADH concentration, which occurs in a com-
pletely randomized way and does not keep any rela- 3.9.7. ETIOLOGY
tion to modifications in plasmatic osmolality. The A In many circumstances SIADH remains as a pre-
pattern accounts for approximately 35% of patients sumptive diagnosis because clear information on the
with SIADH. A second group, consisting of about main points of the syndrome is missing. The small
one third of the cases, presents a readjustment in cell lung carcinoma is probably the most common
Chapter 27 I Hypothalamic Disease 495

neoplastic cause of the syndrome. In a few well- Table 5

documented cases, ADH has been shown in tumoral Causes of ADH excess (SIHAD)
extracts, suggesting that the tumor is the source of Central Nervous System Diseases Drugs
ADH. However, not every patient with SIADH asso- Meningitis Cytostatic
ciated with neoplastic diseases present an ectopic pro- Encephalitis Anesthetic
duction of ADH. In these cases, an excessive neuro- Trauma Analgesic
hypophyseal ADH secretion has been observed. Other Ischemic-hypoxic lesion Sedative
studies have suggested that abnormal forms of ADH Tumor Anti-depressive
are secreted by some tumors as observed in extracts Guillain-Barre syndrome Sulfonylureas
of chromatographed tissues in positions where molec- Ventriculoatrial shunt obstruction Causing nausea
ular weight is higher than that of ADH. Acute intermittent porphyria
Thrombosis of skull basis sinus Neoplasias
Trauma may lead to an "interphase" of ADH secre-
Hemorrhage (intracerebral,
tion. Possible presence of this interphase has been subarachnoid)
recently demonstrated in experimental animals with Malformation Postoperative
partial lesions of the hypophyseal stalk of SIADH state
without DI, because the injured stalk is able to avoid
DI, and ADH is released. In the postoperative period, Lung Diseases Trauma
Pneumonia Bums
anesthesia, narcotic and sedative drugs, pain, intesti-
Tuberculosis
nal manipulation, nausea, and circulatory adjustments Neoplasm Endocrine failure
may reduce water excretion for one or several days. Thyroid
In a recent study, the most common cause of hypona- Decrease in left atrium filling Adrenocortical
tremia in the postoperative period was excessive Positive pressure ventilation
administration of glucose solutions. In newborns, Pneumothorax Idiopathic
especially those premature, SIADH is relatively com- Atelectasis
mon because of hypoxic cerebral lesion, frequently Asthma
along with hemorrhage, pneumonia, pneumothorax Arterial duct connection
and atelectasis, meningitis, patent arterial duct con-
nection, and positive pressure ventilation. In chronic hyponatremia there is solute extrusion
3.9.7.1. Clinical and Laboratorial Diagnosis. The from cerebral cells, mainly of NaCI an KCI, by
clinical picture is a combination of signs and symp- membrane transportation processes different from
toms of the primary disease (Table 5) and of hypos- Na-K-ATPase, making osmotic balance between
molality. The most important signs and symptoms cerebral cells and the extracellular medium to be per-
originate from neuromuscular and CNS. By and large, formed with lower increase in cerebral volume. On
the first signs and symptoms to appear are anorexia, the other hand, if there is fast hyponatremia correc-
apathy, confusion, headache, asthenia, abdominal col- tion, the cerebral cells depleted of solute will have a
ics, and cramps in the limbs. In moderate cases, the reduced volume. It is important to note that because
clinical picture includes nausea, vomit and any other of sodium escape, as previously mentioned, edema
kind of neurological abnormality, ranging from is seldom part of SIADH clinical picture.
depressed deep tendon reflexes to pathological True hyposmolality is always because of one out
reflexes, bulbar or pseudobulbar paralysis, and psy- of two entirely different disorders: fluid retention or
chotic behavior. In the most severe cases, seizures, sodium depletion. The clinical history, underlying
coma, and death may occur. Severity depends more disease and physical findings, help in differentiating
on the speed of onset than on sodium levels. Chronic both causes. Primary sodium depletion is invariably
hyponatremia differs from acute in human beings associated to extracellular medium contraction and
regarding two major factors: fluid retention is associated to its expansion. Such
depletion is the result of either extrarenal (gastrointes-
(a) approximately half of the patients with chronic tinal, surgery, and inflammation) or renal losses (natri-
hyponatremia are asymptomatic, even when uretic peptides, mineralocorticoid deficiency, natri-
serum sodium level is lower than 125 mEq/L; uretic medication, or salt-losing nephropathy). In
(b) mortality rate is nearly zero in asymptomatic those cases where clinical distinction between con-
patients and it is about 10-15% in sympto- traction and expansion is difficult, urea and plasmatic
matic patients. protein dosage will be high in sodium depletion. In
496 Part V / Neuroendocrinology

SIADH, plasmatic urea is initially low. In a later risks. Studies with animals show that hyponatremic
stage, urinary sodium may be lower or absent, but females present higher mortality than males, which
the syndrome may be distinct because the patient is seems to be originated from a lower ability of females
unable to retain a sodium load, unless fluid ingestion concerning mechanisms of volume regulation and
is restricted. SIADH cannot be excluded in plasmatic production of high-energy phosphate. In human
hyposmolality associated to a maximally dilute urine, beings, it is not known whether female gender is a
because it may occur in the previously mentioned factor of bad prognosis.
type B. Symptomatic hyponatremia, with serum sodium
below 120 mEq/L, requires immediate treatment.
3.9.8. TREATMENT
Normal or hypertonic saline solution combined with
The primary disease must be treated first, paralleled furosemide is used. Urine induced by this diuretic
with correction of hyponatremia. The way of presents osmolality lower than that of the plasma,
approaching hyposmolality will depend on some pre- and natriuresis determined by it is beneficial, because
viously mentioned factors, such as speed of onset, it decreases risks of extracellular volume expansion.
hyponatremia intensity, and mainly after characteriza- Speed of correction of hyponatremia is a controversial
tion of clinical symptoms. Characterizing a patient topic in the literature as already mentioned. We con-
as symptomatic or asymptomatic may be difficult, sider that correction should be performed in a speed
especially if the primary disease is neurologic and of approximately 0.5 mEq/L/h until serum sodium
symptoms and signs may be confused with water achieves 120 to 125 mEq/L. Cases of higher risks
intoxication. When plasmatic sodium is higher than may be corrected with a speed of increase in sodium
125 mEq/L, very seldom do patients become symp- of 1-2 mEq/L/h. It seems important to avoid sodium
tomatic. In the asymptomatic patients, the first step increment greated that 25 mEq/L in 48 h. The major
to be taken is fluid restriction in order to generate a concern as to quick correction is in the central pontin
negative fluid balance, which is generally attained myelinolysis (CPM), a demyelinization of the pons,
with approximately 700-800 mL per day. Therefore, with destruction of the myelin sheaths, sparing axon
natriuresis decreases and an increase in sodium supply and nucleus. It also may occur in other white matter
may be initiated. Three or five additional grams of brain areas. Clinical characteristics include flaccid
sodium are initially administered, totaling a salt in- quadriplegia or paraplegia, facial paresis, dysphasia,
gestion of approximately 15 g per day. Furosemide dysarthria and coma. By and large patients with CPM
(40-80 mg/day) may be added to this regimen. Com- present further risk factors such as alcoholism or mal-
pliance with fluid restriction is many times difficult nutrition.
because of inappropriate thirst, and sometimes further
therapeutical measures are needed, such as use of
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cell tumors: classification, diagnosis, and mangement. In:
toxicity and thyroid hypofunction; the individual Youmans JR, ed. Neurological Surgery. Philadelphia, PA:
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and adjusted according to lithemia. Demechlocyclin efficacy of non-peptide ADH antagonist OPC-3l260 in
must be used with caution in patients with hepatic fail- SIADH rats. Kidney Int 1993; 44:19-23.
Girard J, Pampalone-Siervo A. Intracranial space-occupying
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New York: Appleton & Lange and Simon & Schuster Business
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and Professional Group, 1991: pp. 735-760.
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lower than 125 mEq/L, need immediate therapy and pituitary. In: DeGroot LJ, ed. Endocrinology. Philadel-
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