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Hypothalamic dysfunction (hypothalamic syndromes) 

Hypothalamic dysfunction (hypothalamic syndromes)
Chapter:
Hypothalamic dysfunction (hypothalamic syndromes)
Author(s):

M. Guftar Shaikh

DOI:
10.1093/med/9780199235292.003.2181
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Introduction

The hypothalamus is a complex area of the brain and is important in co-coordinating signals between the nervous system and the endocrine system, primarily via the pituitary gland. Various processes throughout life, such as birth, puberty, and pregnancy, as well as neurological and psychiatric disorders are regulated by the hypothalamus (1). It influences many hormonal and behavioural circadian rhythms, as well as being involved in the control of body temperature, hunger, and thirst. Damage to the hypothalamus whether it is congenital or acquired will lead to significant clinical morbidity (Box 2.4.1.1). Recent advances in molecular techniques and improved neuroimaging, particularly MRI and positron emission tomography (PET) have given us a better understanding of hypothalamic syndromes and their clinical manifestations.

a Some congenital causes may not manifest themselves until later in life.

It may be very difficult to differentiate between hypothalamic and pituitary disease as the endocrine abnormalities are often similar. As the hypothalamus regulates both endocrine and autonomic function, there is usually a combination of endocrine and neurological disturbance in hypothalamic damage. This includes abnormal behaviour, eating disorders, and thermoregulation.

The hypothalamus consists of a number of different nuclei which have very specific functions and also secretion of hypothalamic hormones and neuropeptides (1). The clinical syndrome will depend on the location and extent of the underlying lesion. The lesion may be very small and only affect specific hypothalamic nuclei which will result in discrete symptoms; however larger lesions, which are more likely, will present with a variety of problems (Fig. 2.4.1.1). The endocrine abnormalities seen in hypothalamic syndromes usually result in pituitary hyposecretion; however due to loss of inhibitory factors hypersecretion can also occur.


Fig. 2.4.1.1 The hypothalamic nuclei network and functions.

Fig. 2.4.1.1
The hypothalamic nuclei network and functions.

Children and adolescents usually present with growth failure and disorders of puberty, which can be both delayed and precious. Adults with hypothalamic dysfunction can present with dementia, disturbances in appetite and sleep, as well as hormonal deficiencies. Causes of hypothalamic damage, particularly the anterior hypothalamus, include tumours such as craniopharyngiomas, optic nerve gliomas, and inflammatory conditions such as histiocytosis and sarcoidosis.

Clinical features

These include both endocrine and nonendocrine neurological features (Box 2.4.1.2). It can be difficult to distinguish between them, as endocrine dysfunction can also lead to hypothermia, lethargy, and abnormalities in sodium and water balance, which may be due to inadequate replacement of pituitary hormones.

Due to the variability of presentation of hypothalamic dysfunction, the clinician needs to maintain a high index of suspicion, particularly when there is a combination of endocrine and neurological abnormalities. A history of cranial surgery, especially pituitary, cranial radiotherapy and trauma to the head are risk factors for hypothalamic damage. Symptoms and signs of hypopituitarism may be due to an abnormality in the hypothalamus rather than the pituitary gland. Visual field defects may indicate a mass lesion causing hypothalamic disturbance.

Biochemical assessment

If there is a suggestion of an endocrinopathy, either at the pituitary or hypothalamic level, basal assessment is essential, although dynamic tests may be more appropriate. In cases of cranial tumours where surgery is imminent, it should be assumed that the patient has adrenocorticotropic hormone (ACTH) deficiency and is treated with glucocorticoids during surgery and the postoperative period. The patient should remain on replacement glucocorticoid therapy until they are well enough for formal dynamic testing, which may be a few months later. Unfortunately, dynamic assessment will not necessarily differentiate between a pituitary and hypothalamic aetiology of the hormonal deficiencies. A thyrotropin-releasing hormone (TRH) test may provide useful information. An exaggerated and delayed rise in thyroid-stimulating hormone (TSH) following administration of TRH suggests hypothalamic disruption. The need for the TRH test has been debated and its usefulness questioned as diagnosis of central hypothyroidism can be made on serial measurements of serum thyroxine alone (2, 3).

Neuroimaging

CT or MR scans are mandatory in the investigation of hypothalamic disorders to exclude mass lesions. Unfortunately no imaging techniques are easily able to diagnose hypothalamic dysfunction, although PET scans using radiolabels have demonstrated the hypothalamus to be involved in the early stages of some neurological disorders, such as Huntingdon’s disease (4). PET scans together with appropriate radiolabels may be more helpful in the future. Advances in MRI such as the use of pulse sequences and perfusion weighted images may allow better evaluation of neuroendocrine disorders (5). In a study by Manuchehri and colleagues, where prolactinomas were treated with dopamine antagonists, reductions in vascularity preceded tumour shrinkage (6). This form of imaging may provide earlier information about response to treatment and the need to intensify therapy.

Endocrine abnormalities

Hypothalamic hormone deficiencies consist of TRH, corticotropin-releasing hormone (CRH), gonadotropin-releasing hormone (GnRH), and growth hormone-releasing hormone (GHRH). These can occur in isolation or in combination and without obvious hypothalamic damage, particularly if the abnormality is due to a genetic defect, such as GHRH receptor gene. The management of these hypothalamic hormone deficiencies is no different from pituitary hormone deficiencies. Hormone replacement therapy in the form of thyroxine, glucocorticoids, sex steroids, and growth hormone is recommended if indicated. In addition, desmopressin may also be needed if there is evidence of central diabetes insipidus.

Disruption of hypothalamic hormone secretion may occur due to psychosocial disorders. Children subjected to severe emotional distress can demonstrate low growth hormone levels on testing, however, when the child is placed in a better environment their growth hormone levels return to normal (7). Another situation where reversible hypothalamic disruption occurs is in anorexia and severe weight loss. This results in secondary amenorrhoea, and menstruation returns after appropriate weight gain. A similar situation is also seen in female athletes. The majority of hormonal problems result due to loss of function, however, hypersecretion of pituitary hormones may also occur in hypothalamic disease.

Excessive GHRH secretion, due to a tumour, has been reported to cause acromegaly and gigantism. Increased secretion of GnRH will result in precocious puberty in children and may be due to a hypothalamic hamartoma. An underlying cause must always be sought in boys with precocious puberty, although a cause may not always be found in girls.

Hyperprolactinaemia can occur due in hypothalamic dysfunction, possibly as a result of reduced dopamine secretion. Raised prolactin levels may present with delayed puberty in children, together with galactorrhoea in girls and gynaecomastia in boys. Headaches and visual disturbance may also be a presenting feature. The prolactinomas may be part of an inherited syndrome such as multiple endocrine neoplasia type 1 (MEN 1). Prolactin level needs to be measured in any patient with a pituitary mass, as treatment for a prolactinoma is primarily medical and not surgical.

Eating disorders

Several hypothalamic sites, including the arcuate nucleus (ARC), ventromedial nucleus (VMH), paraventricular nucleus (PVN), and the lateral hypothalamic nucleus (LHN) are important in regulating feeding behaviour (8). The obesity may be due to genetic causes resulting in abnormal hypothalamic signalling or more commonly due to damage to the hypothalamus from tumours, either directly or as a result of subsequent surgery and/or radiotherapy. Damage to the LHN results in aphagia and even death by starvation, whereas damage to the other sites, particularly the VMH, leads to hyperphagia and obesity. A variety of orexigenic and anorectic peptides are produced within these hypothalamic nuclei and it is these signals that influence the neural circuitry within the hypothalamus, resulting in energy homoeostasis (8).

Leptin, secreted by adipose tissue, together with insulin, leads to the suppression of appetite via the hypothalamus, by inhibiting neuropeptide Y (NPY) and Agouti-related protein (AgRP) expression (9). NPY is a potent stimulator of food intake and this is confirmed in animals (9). Melanocortin-concentrating hormone (MCH) and AgRP also stimulate food intake (8, 9). AgRP blocks the binding of α‎-melanocyte stimulating hormone (α‎-MSH) to melanocortin receptors and reduces the anorectic activity of the melanocortin pathway (10). The increased adiposity signals, leptin and insulin, lead to neuronal synthesis of peptides such as α‎-MSH and cocaine and amphetamine related transcript (CART), which promote negative energy balance through the α‎-melanocortin pathway, by either reducing food intake or increasing energy expenditure (8, 9).

Anorexia/failure to thrive

Although anorexia nervosa is a psychiatric illness which can be related to hypothalamic dysfunction, it is important to remember hypothalamic disease may present with symptoms of anorexia. Neuroimaging may be needed to exclude hypothalamic tumours. The endocrine abnormalities associated with anorexia nervosa are not always reversible despite adequate weight gain (11).In childhood, diencephalic syndrome may present with severe failure to thrive. This is despite a normal or even excessive calorie intake. Features include emaciation, hyperactivity, and inappropriate euphoric effect. The syndrome is a result of a hypothalamic tumour near the optic chiasm, usually a glioma, and can be associated with neurofibromatosis 1. The prognosis for these children is very poor and even if they survive initially, hyperphagia and obesity usually occur.

Obesity

Hypothalamic obesity is severe and difficult to manage. Craniopharyngioma patients and patients who have received surgery and/or radiotherapy for treatment of their tumours are most at risk of developing hypothalamic damage and subsequent obesity (1214). These individuals are also at increased risk of developing the metabolic syndrome due to the obesity and growth hormone deficiency (15). The degree of hypothalamic damage on neuroimaging is also a significant risk factor for the development of obesity (16). It is clear that damage to the VMH in rats leads to hyperinsulinaemia, hyperphagia, and insulin resistance, although the exact pathogenesis remains unclear (17). The autonomic hypothesis proposed by Bray et al. (18) suggests a reduction in sympathetic activity and an increase in parasympathetic activity occurs after VMH lesioning. A similar hypothesis proposed by Lustig is that damage to the VMH results in disinhibition of vagal tone at the pancreatic level (19, 20), leading to insulin hypersecretion by the pancreas and resultant obesity.Lustig and colleagues have used octreotide, a somatostatin receptor agonist, to inhibit β‎ cell insulin release by the pancreas. This demonstrated a reduction in weight gain and body mass index (BMI), together with improvements in insulin responses (21). These initial results were promising, however, more recent studies using a long acting form of octreotide have been variable and disappointing (22). It important to remember octreotide is expensive and not without complications.

It is still not clear whether the hyperinsulinaemia seen in these individuals is the primary driving force behind the obesity or whether the increased adiposity causes the hyperinsulinaemia. Some studies have shown no differences in insulin levels between hypothalamic obese individuals and those with simple obesity suggesting hyperinsulinaemia is a secondary phenomenon (23).

Another hormone which influences appetite is ghrelin. This is the hormone of hunger, with elevated levels during fasting. Elevated ghrelin levels have been reported in Prader–Willi syndrome, however, Kanumakala and colleagues demonstrated ghrelin levels were not raised in obesity following hypothalamic damage (24), suggesting it is not ghrelin that causes the hyperphagia.

Receptors within the hypothalamus may be affected as a result of the surgery and/or the radiation. Hypothalamic insulin receptors are important in the regulation of food intake. Knockout mice without central nervous system insulin receptors (25) and mice where hypothalamic insulin receptors are reduced (26) also develop hyperphagia and obesity.

Leptin levels have been shown to be elevated following hypothalamic obesity. This appears to be more than a reflection of the underlying obesity as the leptin levels are much higher compared to simple obese controls (23). Dysfunctional insulin and leptin receptors within the hypothalamus may have a role in hypothalamic obesity. As well as the leptin pathway, another pathway that is important in weight regulation is the melanocortin pathway.

The melanocortin pathway accounts for the gene causing the majority of genetic obesity. The mutated gene, which was discovered more than 100 years ago, is called Agouti or Agouti-signalling protein (ASIP) (27). It was not until more recently that its effect on obesity was discovered. ASIP blocks the binding of α‎-MSH to melanocortin receptor 1 (MC1R). ASIP was found to also block the binding of a-MSH to MC3R and MC4R, which are found within the hypothalamus and regulate food intake. MC4R mutations have been mainly identified through studies in severely obese children and account for the commonest form of genetic obesity (28).

α‎-MSH is produced by proteolysis of pro-opiomelanocortin C (POMC). As α‎-MSH binds to MC3R and MC4R to reduce food intake, mutations in POMC also result in obesity. Children with certain POMC mutations also have adrenal insufficiency, as α‎-MSH is composed of the first 13 amino acids of ACTH, and have red hair, as binding of α‎-MSH in skin (MC1R) is responsible for the hair colour (29, 30). POMC needs to be converted into different hormones including α‎-MSH by a protease prohormone convertase-1 (PCSK1). Mutations in PCSK1 have been reported causing hypogonadism, adrenal insufficiency, as well as obesity (31).

The genetic mutations in MC3R and MC4R, which are found within the hypothalamus, regulate food intake (27). These are expressed within the brain and result in abnormal signalling within the hypothalamus. More recently, the endocannabinoid system has been shown to be involved in appetite and energy metabolism. The cannabinoid receptors within the hypothalamus have been shown to stimulate food. Receptor antagonists have been shown to reduce appetite, together with improvements in diabetic control which cannot be due to reductions in weight alone, suggesting the cannabinoid system has an effect on a variety of organs and metabolic processes. Unfortunately, one of these drugs, rimonabant, was recently withdrawn due to an increased suicide risk.

Energy expenditure

The hypothalamus is not only involved in appetite control, but also energy expenditure (32, 33). The resting metabolic rate (which is highly variable between individuals but is consistent within individuals (34)) typically accounts for 50–65% of total daily expenditure in sedentary individuals and can be influenced by the hypothalamus, primarily through the sympathetic nervous system. Leptin deficiency, either primarily or receptor abnormalities may lead to impaired sympathetic activity and decreased thermogenesis, and although this has been demonstrated in rodents, it is unclear whether or not this occurs in humans (35). Adipocytokines, in particular adiponectin, also seem to increase energy expenditure in animals (36). Damage to the hypothalamus has been shown to result in a reduced basal metabolic rate and physical activity which will further exacerbate the obesity (37). Supra-physiological doses of thyroxine have used in the treatment of hypothalamic obesity (38).

Autonomic dysfunction

The hypothalamus and in particular the paraventricular nucleus has been shown to be an important regulator of the autonomic nervous system and can also influence gastrointestinal and cardiac function. The anterior nuclei, such as the medial preoptic nucleus, reduce heart rate and blood pressure through parasympathetic activity, whereas the posterior nucleus increases blood pressure by increasing sympathetic activity. This autonomic stimulation is mediated via a complex integrated circuitry, with influences also from nonendocrine neurons (39).Recently, a number of cytokines and hormones have been shown to stimulate neurons within the hypothalamus. This includes angiotensin II and adiponectin, which have an effect on blood pressure and glucose metabolism, respectively. Drugs which modify angiotensin II action, such as angiotensin-converting enzyme inhibitors may have a role within the hypothalamus and not just a direct cardiac action (39).

The autonomic nervous system through the hypothalamus may influence the cortisol-cortisone shuttle. Tiosano and colleagues demonstrated enhanced activity of 11β‎-hydroxysteroid dehydrogenase-1 (HSD) in patients with hypothalamic obesity, suggesting the hypothalamus regulates the peripheral activity of 11β‎-HSD (40). The increased conversion of cortisone to the active metabolite cortisol, possibly through CRF and ACTH deficiency, together with increased sympathetic tone (41), may lead to increased side effects of glucocorticoids, one of which is obesity.

Fluid balance and thirst

Osmoreceptors within the hypothalamus are involved in the regulation of sodium and water balance through the secretion of antidiuretic hormone (ADH). Deficiency of ADH leads to diabetes insipidus, causing polyuria and polyuria, which further result in hypernatraemia. The patient may maintain normal serum sodium levels and serum osmolality by drinking excessively through thirst. If the patient loses the perception of thirst, a fixed daily fluid requirement is needed in addition to desmopressin therapy. It is important to remember ADH deficiency may not manifest itself if there is also underlying ACTH deficiency. Diabetes insipidus will become evident once glucocorticoid therapy is initiated.

Disturbances in hypothalamic function may also lead to the syndrome of inappropriate ADH (SIADH), resulting in hyponatraemia, but this is usually transient.

Regulation of sleep

Sleep can be altered due to hypothalamic damage. There are both sleep promoting and arousal systems within the hypothalamus. The posterior hypothalamus is involved in the arousal network, whereas neurons in the preoptic hypothalamus have been shown to secrete the inhibitory neurotransmitter γ‎-aminobutyric acid (GABA) resulting in modulation of the arousal system, leading to sleep promotion and maintenance (42). Damage to the anterior hypothalamus will result in insomnia, and damage to the posterior hypothalamus will result in a hypersomnolent state.

Abnormal sleeping patterns will have an effect not only on the individual patient but also on the rest of the family, particularly parents and other siblings. If there is significant problems sleeping, a trial of melatonin is recommended, however, it is not effective in all patients, which may be related to the degree of hypothalamic disruption. If excessive sleepiness, particularly during the day is a problem, central nervous system stimulants such as modafinil can be used, although it should be used with caution as long-term use may result in dependence.

Recently discovered neuropeptides known as orexins and hypocretins may be involved not only in sleep, as they promote wakefulness, but they may also be involved in breathing. Mice lacking the orexin gene have been found to be less responsive to carbon dioxide induced increases in breathing, together with more sleep apnoeas (43). Orexins may have a role in the treatment of respiratory disorders. Disruption of sleep will also have an impact on circadian rhythms.

Temperature regulation

The anterior/preoptic and dorsomedial areas of the hypothalamus have been shown to be involved in thermoregulation. The anterior area, which contains the warm sensitive neurons, seems to the primary thermosensitive region (44). Activity within these neurons results in a fall in temperature, whereas activity in the dorsomedial nucleus leads to a rises in core temperature. The exact mechanisms by which the hypothalamus maintains core temperature remains unclear. Hypothermia can be a feature of hypothalamic disease and may reflect damage to the posterior hypothalamus (45). Paroxysmal hypothermia may also occur in association with hyperhidrosis, and is characterized by episodes of hypothermia with excessive sweating. This may be due to a resetting of the temperature set point or possibly due to increased firing of the warm sensitive neurons resulting in excessive sweating and hypothermia. There has been some beneficial effect of using muscarinic cholinergic receptor blockers to reduce sweating, such as oxybutynin or glycopyrrolate. Other drugs which have been used include clonidine, chlorpromazine, and cyproheptadine, although these centrally acting drugs have been reported to have varying success (45). It is important to ensure optimum pituitary hormone deficiencies before considering any of the above drugs.

Genetic/syndromic causes of hypothalamic dysfunction

A number of signalling molecules and transcription factors have been reported to be involved in the development of the hypothalamus and pituitary gland (46). These are discussed in more detail in Chapters 2.1 and 2.2. Although most of these affect the pituitary gland, some also lead to hypothalamic dysfunction.

Kallmann’s syndrome

Classic Kallmann’s syndrome is characterized by hypogonadotropic hypogonadism and is associated with anosmia/hyposmia and occasionally optic features. It can be inherited as an X-linked recessive disorder due to an abnormality in the in the KAL1 gene, which maps to chromosome Xp22.3. This gene encodes anosmin-1, which is required to promote migration of GnRH neurons into the hypothalamus. This results in hypothalamic GnRH deficiency. Other genes which have been implicated in Kallmann’s syndrome include fibroblast growth factor receptor 1 (FGFR1) gene and mutations in the pro-kineticin receptor-2 gene (PROKR2) and its ligand prokineticin 2 (PROK2) (47).

Prader–Willi syndrome

This syndrome is due to a paternal deletion of chromosome 15 or unimaternal disomy. It is associated with dysmorphic features, together with short stature, hypotonia, and hypogonadism. These children develop hyperphagia, despite having difficulty in feeding during early infancy. Growth hormone is licensed for these children primarily to improve body composition, however, provocative testing may demonstrate growth hormone deficiency possibly due to hypothalamic dysfunction (48).

Septo-optic dysplasia

This is a triad of absent septum pellucidum, optic nerve hypoplasia, and hypopituitarism, although for diagnosis only two of the triad are required. The spectrum of the disorder is variable with varying degrees of visual impairment and pituitary deficiencies. Vascular insults during embryonic development have been implicated, together with maternal drug abuse. Mutations in HESX1 have been found in children with septo-optic dysplasia, however this accounts for a very small proportion (49). These patients can have significant hypothalamic dysfunction in the form of hyperphagia, sleep disturbance and temperature regulation as well as hormonal deficiencies. The degree of hypothalamic dysfunction is not necessarily related to the anatomical abnormality seen on neuroimaging (50).

Acquired causes of hypothalamic dysfunction

These are primarily tumours such as craniopharyngiomas, germinomas, and hamartomas and are discussed in more detail in other chapters. Other causes include inflammatory conditions such as histiocytosis and sarcoidosis. Histiocytosis is a granulomatous disorder with different clinical types and can affect skin, muscle and bone, as well as other organs. Diabetes insipidus can be a presenting feature. Pituitary hormones deficiencies although less common can occur and are usually permanent. Treatment consists of glucocorticoids and or chemotherapy depending on the response to initial therapy and histological findings at diagnosis.

Sarcoidosis, which is a systemic disease, can be associated with hyperprolactinaemia. The exact reasons for elevated prolactin levels remain unclear, but it may be due to production by T lymphocytes causing disruption of the hypothalamic dopaminergic feedback mechanism. Thyroid disease both hypothyroidism and hyperthyroidism is also common in women with sarcoidosis.

Radiotherapy for treatment of nasopharyngeal and intracranial tumours is an important cause of hypothalamic damage (51). The effects of radiotherapy on hypothalamic function may not become evident until several years after treatment. The damage to the hypothalamus is dose dependent and also the field of therapy. Somatotrophs are the most sensitive cells to radiotherapy and children present with growth failure, followed by damage to gonadotrophs, which usually presents with delayed puberty. However children who have cranial tumours may also develop precocious puberty.

Traumatic brain injury is now increasingly recognized as a cause of growth hormone deficiency and other pituitary hormones (52). This may be due to damage at the hypothalamic or pituitary level, or a combination of both.

Management

Management of hypothalamic dysfunction is primarily aimed at replacing hormonal deficiencies. Standard replacement therapy in terms of thyroxine, glucocorticoids, and, where appropriate, growth hormone and sex steroids should be initiated. Desmopressin may also be required. It is important to remember that the endocrinopathies may evolve with time in certain hypothalamic syndromes, particularly in those individuals who have had cranial tumours and subsequent radiotherapy. If glucocorticoid deficiency is suspected, replacement therapy should be started without delay, particularly if surgical intervention is urgently needed. Surgery for hypothalamic dysfunction may be appropriate, especially where tumours are responsible for the hypothalamic syndrome. The nonendocrine manifestations are more difficult to manage and usually involve a trial of therapy (Table 2.4.1.1).

Table 2.4.1.1 Medications used in the management of hypothalamic dysfunction (21, 38, 45, 53, 54)

Obesity

Octreotide

Triiodothyronine

Dextroamphetamine

Rimonabanta

Fenfluraminea

Temperature

Oxybutynin

Regulation

Glycopyrrolate

Clonidine

Chlorpromazine

Cyproheptadine

Sleep disorders

Melatonin

Modafinil

a These drugs are no longer available.

Octreotide and sibutramine has been used in the treatment of hypothalamic obesity with some success (21, 53). Triiodothyronine has been shown to be of benefit in a few individuals (38). Future strategies to increase energy expenditure, in particular resting metabolic rate, together with the manipulation of neuropeptides involved in appetite and weight regulation may lead to improvements in the management of hypothalamic obesity.

The autonomic dysfunction of hypothalamic syndromes is particularly difficult to manage and usually involves a trial of medication, some of which have already been mentioned. Unfortunately a lot of these therapies are not very successful. Better understanding of the neuropeptides involved in hypothalamic dysfunction, such as orexins, may result in pharmacotherapies in the future.

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