Hypothalamic Syndromes

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Chapter 5

Hypothalamic Syndromes

Glenn D. Braunstein

The hypothalamus houses multiple nuclei along with afferent and efferent nerve fibers that connect the hypothalamus to the various portions of the brain and brainstem. It is divided into four regions: from anterior to posterior, the preoptic, supraoptic, tuberal, and mamillary regions; and three zones: laterally from the third ventricle, the periventricular, medial, and lateral 1–4 zones (Table 5-1, Figs. 5-1 and 5-2).

Table 5-1

Major Hypothalamic Nuclei

From Braunstein GD: The hypothalamus. In Melmed S (ed): The Pituitary, 2nd ed. Cambridge, MA: Blackwell Scientific, 2002, pp 317–348.

FIGURE 5-1 Schematic representation of lateral brain section demonstrating hypothalamic nuclei. Dashed lines represent the frontal (coronal) section planes illustrated in Figures 5-2 and 5-3. 1, preoptic nucleus; 2, paraventricular nucleus; 3, anterior hypothalamic areas; 4, supraoptic nucleus; 5, arcuate nucleus; 6, dorsal hypothalamic area; 7, dorsomedial nucleus; 8, ventromedial nucleus; 9, posterior hypothalamic area; 10, mamillary body; 11, optic chiasm; 12, optic nerve. (From Braunstein GD: The hypothalamus. In Melmed S [ed]: The Pituitary, 2nd ed. Cambridge, MA: Blackwell Scientific, 2002, pp 317–348.)

FIGURE 5-2 Frontal (coronal) sections of the hypothalamic regions. A, Preoptic region (frontal section plane 1 in Fig. 5-1). B, Supraoptic region (frontal section plane 2 in Fig. 5-1). C, Tuberal region (frontal section plane 3 in Fig. 5-1). D, Mamillary region (frontal section plane 4 in Fig. 5-1). (From Braunstein GD: The hypothalamus. In Melmed S [ed]: The Pituitary, 2nd ed. Cambridge, MA: Blackwell Scientific, 2002, pp 317–348.)

The hypothalamus is responsible for many of the body’s homeostatic mechanisms, including water metabolism, temperature regulation, appetite control, the sleep/wake cycle, circadian rhythms, and control of the sympathetic and parasympathetic nervous systems. In addition, this area has activity in regard to emotional expression, behavior, and memory. Finally, the hypothalamus is essential to the neuroendocrine control of anterior pituitary function. Table 5-2 lists the various functions of the hypothalamus, the hypothalamic nuclei or hypothalamic regions that have been identified as being responsible for these functions, and the disorders that result from either destructive or stimulatory lesions in or around the nuclei or region.^1,4–25

Table 5-2

Hypothalamic Functions, the Nuclei or Regions Involved with the Specific Functions, and the Disorders Resulting from Stimulatory or Destructive Lesions in the Regions

SIADH, Syndrome of inappropriate secretion of antidiuretic hormone.

Hypothalamic Disorders: Pathophysiologic Principles

First, the small overall size of the hypothalamus and the close association of the nuclei and nerve tracts mean that a variety of different pathologic processes may give rise to the same signs and symptoms of neurologic and hypothalamic dysfunction.⁴ The spectrum of disorders that can affect the hypothalamus is shown in Table 5-3. Tumors, infiltrative disorders, and infections, among other conditions, frequently give rise to headaches, neuro-ophthalmologic disorders, pyramidal tract or sensory nerve dysfunction, extrapyramidal cerebellar signs, and recurrent vomiting.^9,10 Other common manifestations include gonadal dysfunction (either hypogonadism or precocious puberty), diabetes insipidus, somnolence, dysthermia, and evidence of a caloric imbalance (either with hyperphagia and obesity or anorexia with emaciation).^9,10

Table 5-3

Causes of Hypothalamic Dysfunction

Congenital

Acquired

Developmental malformations

Anencephaly

Porencephaly

Agenesis of the corpus callosum

Septo-optic dysplasia

Suprasellar arachnoid cyst

Colloid cyst of the third ventricle

Hamartoma

Aqueductal stenosis

Trauma

Intraventricular hemorrhage

Genetic (familial or sporadic cases)

Hypothalamic hypopituitarism

Familial diabetes insipidus

Prader-Willi syndrome

Bardet-Biedl and associated syndromes

DIDMOAD syndrome

Pallister-Hall syndrome

Leptin/leptin receptor mutations

Tumors

Primary intracranial tumors

Angioma of the third ventricle

Glioblastoma multiforme

Infiltrative

Immunologic

Idiopathic diabetes insipidus

Paraneoplastic syndrome

Nutritional, Metabolic

Anorexia nervosa

Kernicterus

Wernicke-Korsakoff syndrome

Degenerative

Infectious

Jakob-Creutzfeldt disease

Kuru

Poliomyelitis

Varicella

Cytomegalovirus infection

Vascular

Aneurysm

Arteriovenous malformation

Pituitary apoplexy

Subarachnoid hemorrhage

Trauma

Birth injury

Head injury

Postneurosurgical

Functional

Diencephalic epilepsy

Drugs

Hayek-Peake syndrome

Idiopathic syndrome of inappropriate secretion of antidiuretic hormone (SIADH)

Kleine-Levin syndrome

Periodic syndrome of Wolff

Psychosocial deprivation syndrome

Other

Radiation

Porphyria

Toluene exposure

DIDMOAD, Diabetes insipidus, diabetes mellitus, optic atrophy, deafness.

Modified from Braunstein GD: The hypothalamus. In Melmed S (ed): The Pituitary, 2nd ed. Cambridge, MA: Blackwell Scientific, 2002, pp 317–348.

Second, although exceptions exist, most patients who have a systemic disorder such as Langerhans’ cell histiocytosis, sarcoidosis, tuberculosis, or leukemia will exhibit manifestations of the disease outside the hypothalamus and central nervous system.

Third, a lesion may disrupt a function that is subserved by a hypothalamic nucleus distant from the lesion. Because the afferent and efferent tracts to and from the hypothalamic nuclei traverse other areas of the hypothalamus and brain distant from the nuclei, lesions that affect those tracts may result in dysfunction of several hypothalamic nuclei.

Fourth, most lesions that result in chronic hypothalamic syndromes involve more than one nucleus. As can be seen in Table 5-2, most of the hypothalamic functions are controlled by more than one nucleus, and this redundancy allows some degree of compensation should one nucleus be affected. In addition, most of the nuclei are paired, and destruction of a single nucleus may not be sufficient to result in a clinical syndrome. Thus lesions that affect the basal tuberal region of the hypothalamus (pituitary adenomas with suprasellar extension, optic gliomas, and craniopharyngiomas), are multiple (granulomatous disorders, metastatic tumors, infiltrative disease), or cause enlargement of the third ventricle (aqueductal stenosis, colloid cysts, pinealomas, germ cell tumors, midbrain gliomas) will more likely result in clinical hypothalamic dysfunction than will disorders affecting the more lateral portions of the hypothalamus.

Fifth, the rate of progression of the pathologic process affects the patient’s clinical manifestations. Slowly progressive lesions may give few or no symptoms until they achieve a large size, at which time, altered endocrine function and deterioration of cognitive ability may be present. Small, acute lesions may result in profound clinical manifestations such as alterations in consciousness, thermal dysregulation, and diabetes insipidus.

Sixth, the clinical syndrome due to involvement of a hypothalamic nucleus or tract may differ depending on whether the pathologic lesion is destructive or stimulatory. As an example, chronic, destructive lesions of the preoptic region may result in hypothermia and insomnia, whereas hyperthermia and lethargy may be seen with acute stimulatory lesions.

Finally, the clinical manifestations of the hypothalamic disease depend in part on the age of the patient. Thus prepubertal gonadotropin deficiency results in sexual infantilism, whereas in the postpubertal state, regression of secondary sexual characteristics (but not disappearance) occurs. Similarly, prepubertal growth hormone deficiency due to a hypothalamic lesion disturbing growth hormone–releasing hormone (GHRH) function results in short stature, whereas a similar lesion occurring in an adult may manifest only as adult growth hormone deficiency syndrome.

Manifestations of Hypothalamic Disease

Disorders of Water Metabolism

Central Diabetes Insipidus

Complete or partial central diabetes insipidus results from (1) destruction of the antidiuretic hormone (ADH)-producing magnocellular neurons in the supraoptic and paraventricular nuclei or (2) interruption of the transport of ADH through their axons, which terminate in the pituitary stalk and posterior pituitary. Diabetes insipidus is relatively common in patients with chronic hypothalamic disorders, being found in approximately 35% of such patients.9,10 It also is frequently found in patients with acute insults to the hypothalamus or pituitary stalk, as is seen in vascular accidents and neurosurgical trauma. Obesity and hypogonadism frequently are present in patients with diabetes insipidus due to tumors or infiltrative disorders (Fig. 5-3).

FIGURE 5-3 Clinical findings associated with hypothalamic lesions located at various anatomic sites. Clinicopathologic correlation based on multiple studies.15–25A, Corresponds to region depicted in Figure 5-2A. B, Corresponds to region depicted in Figure 5-2C. C, Corresponds to section depicted in Figure 5-2D. (From Braunstein GD: The hypothalamus. In Melmed S [ed]: The Pituitary, 2nd ed. Cambridge, MA: Blackwell Scientific, 2002, pp 317–348.)

The majority of patients with diabetes insipidus have idiopathic or familial diabetes insipidus associated with gliosis of the supraoptic and paraventricular nuclei.²⁶ Approximately one third of patients with idiopathic diabetes insipidus have detectable anti-ADH–producing cell antibodies, suggesting an autoimmune cause.²⁷ Autosomal-recessive, X-linked-recessive, and autosomal-dominant forms of familial diabetes insipidus have been described. In the more common autosomal-dominant form, nucleotide deletions or substitutions in the ADH gene on chromosome 20 have been identified.²⁸ The DIDMOAD syndrome (Wolfram’s syndrome) represents a rare autosomal-recessive form of central diabetes insipidus (DI) associated with type 1 diabetes mellitus (DM), optic atrophy (OA), bilateral sensorineural deafness (D), and occasionally ataxia and autonomic neurogenic bladder.²⁹ Diabetes insipidus is a frequent manifestation of suprasellar and pineal germinomas, sarcoidosis, lymphocytic infundibuloneurohypophysitis, and the chronic disseminated form of Langerhans’ cell histiocytosis.^30–37

Wolff and colleagues ⁴⁴ described a syndrome of hyperthermia associated with shaking chills, fever, hypertension, vomiting, and peripheral vasoconstriction that occurred cyclically at 3-week intervals, without a pathologic lesion in the hypothalamus being found. Similar paroxysms of hyperthermia have been noted in other patients without the cyclicity, and together these episodes may represent a variant of diencephalic epilepsy.^6,44,45

Between 0.02% and 2.4% of patients receiving neuroleptic drugs develop the neuroleptic malignant syndrome (NMS), which is characterized by hyperthermia to 38°C or higher; severe extrapyramidal signs, including “lead-pipe” muscle rigidity and tremor; signs of autonomic nervous system dysfunction such as pallor, tachycardia, arrhythmias, blood pressure lability, and diaphoresis; and changes in mental status, including mutism, delirium, and coma.⁴⁶ All antipsychotic medications have been reported to cause NMS, and most evidence suggests that disruption of dopamine neurotransmission by neuroleptic-induced dopamine receptor blockade is the major pathophysiologic abnormality in susceptible individuals. Indeed, the greater the potency of the neuroleptic in regard to its dopamine D₂-receptor antagonism activity, the greater the frequency of NMS occurrence.⁴⁶ NMS is successfully treated with a variety of dopamine agonists. Injury to the preoptic medial and tuberal nuclei has been demonstrated at autopsy, as has a depletion of hypothalamic norepinephrine concentrations.⁴⁷ The syndrome generally begins within 2 weeks of initiating the neuroleptic and evolves over a 24- to 72-hour period. The most common complication is rhabdomyolysis, which may result in myoglobinuria and acute renal failure. The mortality of this syndrome is currently less than 10%, which reflects increased recognition of the disorder and initiation of prompt therapy.⁴⁶

The serotonin syndrome is closely related to NMS and presents with the triad of altered mental status (somnolence, confusion, agitation, seizures, and coma), autonomic instability (fever, diaphoresis, tachycardia, hypo- or hyperthermia, mydriasis), and abnormal neuromuscular activity (myoclonus, rigidity, hyperreflexia). Any drug or combination of drugs which elevates the concentration of serotonin in the central nervous system can cause the syndrome. These include selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants, monamine oxidase inhibitors, cocaine, and amphetamines. These drugs either directly or indirectly activate thermogenesis via the hypothalamus.⁴⁶

Hypothermia

Large, destructive lesions of the anterior or posterior hypothalamus may result in inability to generate heat through vasoconstriction and muscular shivering. This occurs in 10% to 15% of patients with a variety of hypothalamic lesions, especially neoplasms, infiltrative disorders, and infections.9,10,13 It also has been noted in patients with Parkinson’s disease and Wernicke’s encephalopathy, which are associated with lesions in the posterior hypothalamus and mamillary bodies, respectively.^48,49

Diencephalic autonomic epilepsy refers to episodic or paroxysmal hypothermia during which the body temperature decreases to 32°C or less over minutes to days, along with evidence of autonomic nervous system dysfunction, including flushing, sweating, hypotension, bradycardia, salivation, lacrimation, pupillary dilation, Cheyne-Stokes respiration, nausea, vomiting, asterixis, ataxia, and obtundation.6,15,50–53 Electroencephalographic (EEG) abnormalities occur during the episodes. Autopsy studies have shown gliosis and loss of the arcuate nucleus and premamillary area in some patients, whereas others have been found to have tumors involving the floor and lower portion of the third ventricle.^15,50 The corpus callosum has been found to be absent in approximately half of patients with episodic hypothermia; these individuals may also exhibit diabetes insipidus, reset osmostat, growth hormone deficiency, hypogonadism, or precocious puberty (Shapiro’s syndrome).⁵⁴

Poikilothermia

When both the heat-loss and heat-conserving homeostatic mechanisms are impaired, wide fluctuations of body temperature might take place without the patient’s experiencing thermal discomfort. This condition, known as poikilothermia, is found with both anterior and posterior hypothalamic destruction, as well as in patients with large lesions that may involve the posterior hypothalamus and rostral mesencephalon.6,9,10 Rarely, patients with Wernicke’s encephalopathy may experience poikilothermia.⁶

Disorders of Appetite Control and Caloric Balance

Hypothalamic Obesity

Approximately 25% of patients with structural hypothalamic lesions exhibit hyperphagia and obesity.9,10 Usually, the patients have lesions involving a large portion of the hypothalamus, although bilateral destruction of only the ventromedial nucleus may lead to hypothalamic obesity.^{1,9,10,17,18,22,25,55} The majority of patients harbor a neoplasm, especially craniopharyngioma, with a minority having inflammatory or granulomatous processes, a history of trauma, or infiltrative disorders.⁵⁵ Common clinical findings in these patients include headaches, visual abnormalities, hypogonadism, diabetes insipidus, and somnolence. Less commonly, behavioral abnormalities, such as antisocial behavior or sham rage, and seizures may be present.⁵⁵ Hypothalamic obesity also is found with defects of the leptin and leptin receptor genes, the melanocortin 4 receptor gene, and the proopiomelanocortin gene.^56–59