Endocrine Diseases and the Brain

INTRODUCTION

Endocrine secretions and disorders of metabolism have a profound influence on the nervous system. Disturbances of consciousness and cognition along with a variety of other neurologic symptoms may accompany primary endocrine diseases. In addition, endocrine secretions may influence the expression of neurologic disorders such as migraine, epilepsy, or movement disorders. This chapter considers common endocrine conditions that may cause important neurologic symptoms.

PARATHYROID DISEASE

HYPERPARATHYROIDISM

Epidemiology

Primary hyperparathyroidism is the most common cause of hypercalcemia. The most recent estimated incidence was approximately 22 cases per 100,000 per year. The incidence peaks in the seventh decade and there is a fivefold excess of women in those older than 75 years. The incidence is similar in men and women before 45 years of age. A single-gland adenoma secreting excess parathyroid hormone (PTH) is the most common cause (75% to 85%).

Pathobiology

PTH regulates calcium by direct effects on kidney and bone and indirect effects on the gastrointestinal tract. PTH secretion, in turn, is regulated by ionized calcium concentration in extracellular fluid. Thyrocalcitonin and vitamin D also play important roles in calcium metabolism. The principle effects of PTH on the nervous system are via calcium regulation. However, PTH receptors occur in the brain and an endogenous neuropeptide is the natural ligand. Their exact function is uncertain.

Clinical Features

The classic syndrome of hyperparathyroidism is hypercalcemia with a combination of renal lithiasis, osteitis, and peptic ulcer disease (“stones, bones, and abdominal groans”). However, with the ease of determining serum calcium concentration by routine automated blood chemistry tests, the diagnosis is frequently made with minimal clinical symptoms and the classic triad is rarely seen today. Currently, it is estimated that 70% to 80% of individuals have no symptoms or signs of disease at the time of diagnosis.

Common symptoms include fatigue and subjective weakness. Mental status changes include impaired memory, personality changes, affective disorders, delirium, and psychosis. Elderly patients may be particularly susceptible to the effects of hypercalcemia. Parkinsonism and a syndrome resembling motor neuron disease reversing with parathyroid surgery have been described. “Brown tumors” seen in osteitis fibrosa cystica may cause myelopathy. Neuromuscular symptoms include proximal weakness, muscle pain and stiffness, and paresthesias. Tendon reflexes may be normal or hyperactive.

Diagnosis

The initial diagnosis typically occurs by finding hypercalcemia with hypophosphatemia on routine laboratory screening. This will be followed by an elevated PTH level. Differential diagnosis includes other causes of hypercalcemia, including drugs or conditions causing secondary hyperparathyroidism (e.g., renal failure) or familial hypocalciuric hypercalcemia. Hypercalcemia with low or undetectable PTH levels may suggest cancer-associated hypercalcemia mediated by PTH-related protein, or alternatively, ectopic production of PTH. Electromyography (EMG) and muscle biopsy can show evidence of myopathic or neuropathic disease. Brown tumors show variable intensities on T2-weighted images with intense enhancement on T1-weighted contrast studies. Fluid-filled cysts may be detected.

HYPOPARATHYROIDISM

Epidemiology

Hypoparathyroidism occurs most commonly after thyroidectomy (˜1% to 2 % with experienced endocrine surgeons) or other neck surgery. Autoimmune hypoparathyroidism is the next most common cause. Hypoparathyroidism may also be a feature of inherited disorders (e.g., Kearns-Sayre syndrome or DiGeorge syndrome) or glandular destruction from infiltrative processes or radiation. An estimated 60,000 individuals may have chronic hypoparathyroidism in the United States.

Pathobiology

Hypoparathyroidism is due to deficiency of PTH or lack of peripheral response to PTH (pseudohypoparathyroidism). The latter results from abnormal PTH receptors, defects in receptorlinked enzyme activity, or circulating antagonists. Chronic PTH
deficiency has profound effects on the skeleton, and hypoparathyroidism disrupts normal calcium and phosphorus metabolism. Intracranial calcifications occur in vascular and perivascular locations. The action of PTH in brain is unknown but is hypothesized to be a cause of behavioral deficits seen in some forms of hypoparathyroidism.

Clinical Features

Tetany is the most distinctive sign that may be manifested by carpopedal spasm. Latent tetany can be demonstrated by contracture of the facial muscles on tapping the facial nerve in front of the ear (Chvostek sign) or by evoking carpal spasm by inducing ischemia in the arm with an inflated blood pressure cuff (Trousseau sign). Patients may also present with paresthesias and cramps, and if hypocalcemia is acute, may manifest with seizures, bronchospasm, laryngospasm, or cardiac arrhythmias. Seizures are usually generalized, tend to be frequent, and respond poorly to anticonvulsant drugs.

Intracranial calcifications are common in hypoparathyroidism. The basal ganglia are the predominant site for calcium deposition, but other regions such as the cerebellum may be affected. The calcifications are usually not associated with symptoms, but cognitive impairment and a variety of hypokinetic (parkinsonism) and hyperkinetic (choreoathetosis, hemiballismus, torticollis) movement disorders have been reported. Increased intracranial pressure may complicate hypoparathyroidism. The mechanism is unexplained. Sensorineural hearing loss and myopathy occur rarely.

Diagnosis

Hypocalcemia with an inappropriate low intact PTH level should lead to the suspicion of hypoparathyroidism. Hypomagnesemia can lower calcium and PTH. Hypocalcemia with low PTH essentially rules out other causes of hypocalcemia, such as vitamin D deficiency, malabsorption syndrome, or renal disease. In pseudohypoparathyroidism, PTH levels will be elevated and there are a variety of associated physical abnormalities. In most cases, there may be a relevant prior surgery or history of some destructive process (e.g., radiotherapy) involving the parathyroid. Autoimmune hypoparathyroidism may present with vitiligo or hypoadrenalism. Other forms of hypoparathyroidism may be associated with developmental anomalies (e.g., DiGeorge syndrome or Kearns-Sayre syndrome).

ADRENAL DISEASE

HYPERADRENALISM

Epidemiology

Excessive secretion of glucocorticoids from the adrenal glands produces Cushing syndrome. However, the most common cause of Cushing syndrome is exposure to exogenous, often supraphysiologic doses of glucocorticoids. The incidence of endogenous Cushing syndrome is 0.7 to 2.4 per million population per year. There are two main forms, corticotropin (adrenocorticotropic hormone [ACTH])-dependent (80%) and ACTH-independent (20%). ACTH-dependent Cushing syndrome (Cushing disease) is primarily due to pituitary tumors hypersecreting ACTH and is addressed in Chapter 115. Approximately 20% of ACTH-dependent Cushing syndrome is due to ectopic production of ACTH, usually from carcinoid tumors or small cell carcinoma of the lung. ACTH-independent Cushing syndrome is usually due to an adrenal tumor.

Pathobiology

Hippocampus, amygdala, and cerebral cortex are rich in glucocorticoid receptors. Global cerebral atrophy occurs with Cushing syndrome. Hippocampal atrophy occurs and hippocampal formation volume is positively associated with performance on cognitive testing. Glucocorticoids decrease protein synthesis and increase protein degradation in muscles.

Clinical Features

The physical examination in Cushing syndrome may demonstrate hypertension, plethoric facies, hirsutism, centripetal obesity, a posterior neck fat pad (buffalo hump), purple abdominal striae, and bruising. Diabetes mellitus (DM), gonadal dysfunction, and osteoporosis are prominent features. Cognitive changes (impaired memory, visual-spatial processing, verbal learning, and language performance) with mood disorders (particularly major depression), myopathic weakness, and headache are the most common neurologic features. Myelopathy or radiculopathy may result from epidural lipomatosis.

Diagnosis

The diagnosis of Cushing syndrome is very challenging and despite the classical clinical manifestations, the presentation can be quite nonspecific. The initial step is distinguishing Cushing syndrome from individuals with Cushing-like states where hypercortisolism is a common feature. These include obesity, depression, or alcoholism. There is no test that has absolute diagnostic accuracy, with first-line screening being a 24-hour urinary free cortisol and overnight dexamethasone suppression test or late night salivary cortisol. After Cushing syndrome has been established, plasma ACTH is measured. If ACTH is elevated, then ACTH-dependent causes should be investigated. If ACTH is suppressed, then adrenaldependent Cushing is suspected. There are many potential pitfalls, thus consultation with an experienced endocrinologist is essential. Adrenal tumors or tumors as a source of ectopic ACTH will require imaging for localization.

Outcome

Evidence suggests that resolution of hypercortisolism does not completely resolve symptoms. After successful surgery, hippocampal volume increased and correlated with the magnitude of decrease in cortisol levels. Caudate volume increase has also been described with improvements in depression, anxiety, and obsessive-compulsive behavior. However, reduced brain volume and cognitive behavioral symptoms may only be partially reversible. Cognitive problems and psychopathology may persist even after long-term serum cortisol normalization.

HYPERALDOSTERONISM

Epidemiology

Hyperaldosteronism is the most common disorder of the adrenal zona glomerulosa with a prevalence of 5% to 20% of patients with resistant hypertension. It is the most common form of secondary hypertension.

Pathobiology

Aldosterone, typically produced by an adrenal adenoma or bilateral adrenal hyperplasia, is inappropriately elevated. The resulting volume expansion causes hypokalemic alkalosis and hypertension, although hypokalemia and hypertension are not generally correlated with aldosterone levels. Activity-dependent conduction block responsive to potassium replacement has been reported with neurophysiologic studies obtained in a patient with primary aldosteronism, weakness, and severe hypokalemia.

Clinical Features

The principle clinical feature is hypertension. There appears to be an excess incidence of stroke in patients with hypertension from primary aldosteronism versus essential hypertension. Hypokalemic alkalosis can lead to muscle weakness, paresthesias, tetany, or paralysis. Recurrent attacks of muscle weakness may simulate periodic paralysis. Paresthesias may occur as a result of the alkalosis. Vertigo may be caused by abrupt fluid and electrolyte shifts. Idiopathic intracranial hypertension has been reported. Many patients may suffer from an anxiety disorder and diminished sense of well-being.

HYPOADRENALISM

Epidemiology

Primary adrenal insufficiency, also known as Addison disease, has a prevalence of approximately 100 per million and an incidence of 5 per million in white populations. Age of diagnosis peaks in the fourth decade with women more frequently affected than men. In developed countries, 80% to 90% is due to autoimmune adrenalitis, occasionally in association with other autoimmune disorders, such as thyroid disease, hypoparathyroidism, or DM. Secondary adrenal insufficiency due to reduced pituitary ACTH has an estimated prevalence of 150 to 280 per million and is also more frequent in women. The peak age is in the sixth decade and is related to therapeutic administration of glucocorticoids.

Pathobiology

Destruction of the adrenal gland results in both corticosteroid and mineralocorticoid deficiency. It also results in dehydroepiandrosterone deficiency, which leads to androgen deficiency in women. In secondary adrenal insufficiency, mineralocorticoid production is preserved. These hormones are critical for sustaining the function of multiple physiologic systems. Glucocorticoids have pleiotropic effects on the nervous system, working at both the genomic level to alter gene expression and protein synthesis and at cell membranes to affect cell permeability and neurotransmitter release. They have effects on brain microstructure and influence production of nerve growth factors. The absence of adrenal hormones has widespread cognitive and behavioral consequences.

Adrenocortical insufficiency due to mutations in the ABCD1 gene results in abnormal metabolism of long-chain fatty acids that characterizes X-linked adrenoleukodystrophy. It may be the only clinical expression in about 10% of cases. In one study, one-third of young boys or men diagnosed with primary adrenal failure (Addison disease) were found to have adrenoleukodystrophy after measurement of long-chain fatty acids (see also Chapter 134).

Clinical Features

In primary adrenal insufficiency, typical systemic features are fatigue, anorexia, weight loss, hypotension, changes in skin, and hair loss. Headache is a common complaint. Mineralocorticoid deficiency produces hyponatremia with salt craving. Cortisol deficiency leads to increased production of melanocyte-stimulating hormone derived from pituitary proopiomelanocortin, which stimulates melanocytes to produce hyperpigmentation. These characteristics distinguish primary from secondary adrenal insufficiency. Cerebral symptoms include apathy, depression, confusion, and rarely, psychosis. Muscle pain and cramping may occur and hyperkalemic periodic paralysis has been observed.

In adrenoleukodystrophy, there is progressive central demyelination with impairment of cognition, vision, hearing, and motor function in children. In a second phenotype with onset in the late 20s, adrenomyeloneuropathy, there is spastic paraparesis and sphincter disturbances.

Diagnosis

Measurement of early morning serum cortisol and plasma ACTH generally separates patients with primary adrenal insufficiency from healthy individuals and those with secondary adrenal insufficiency. The standard short corticotropin test, in which serum cortisol is measured after intravenous ACTH, demonstrates the impairment of the adrenal cortex response to ACTH. In secondary adrenal insufficiency, there may be little difference in baseline hormone measurements from healthy individuals. The insulin tolerance test, which is a powerful activator of the hypothalamic-pituitary axis, remains the gold standard for assessment of secondary pituitary insufficiency. However, this test poses a significant burden on both the patient and the physician and tests such as the short corticotropin test, which capitalizes on the relative adrenal unresponsiveness to ACTH in secondary disease, are used. Because hypoadrenalism may antedate neurologic symptoms in adrenoleukodystrophy or adrenomyeloneuropathy, this diagnosis should be considered in young men with adrenal insufficiency.

PHEOCHROMOCYTOMA

Epidemiology

Pheochromocytomas are rare neuroendocrine tumors with approximately 80% arising from the chromaffin cells of the adrenal medulla. They secrete catecholamines and cause an estimated 0.1% to 0.6% of cases of secondary hypertension.

Pathobiology

Pheochromocytomas may occur sporadically or as part of a hereditary syndrome. Pheochromocytoma may be seen with neurofibromatosis, von Hippel-Lindau disease, ataxia-telangiectasia, Sturge-Weber syndrome, or multiple endocrine neoplasia type 2 consistent with the neuroectodermal origin of the adrenal medulla. It is estimated that 25% are associated with known genetic mutations.

Clinical Features

Hypertension of a moderate or severe degree is characteristic. The hypertension may be paroxysmal or sustained and is associated with palpitations, episodic hyperhidrosis, headaches, and other nonspecific systemic symptoms, such as nausea, emesis, or diarrhea. Anxiety attacks are common. Death may result from cerebral hemorrhage, pulmonary edema, or cardiac failure complicating an acute attack or as a result of sustained hypertension.

Diagnosis

Diagnosis is made by demonstrating increased excretion of catecholamine metabolites in urine and localization of the tumor. Measurement of fractionated plasma or urine metanephrines (or both) is recommended. Food, caffeinated beverages, strenuous physical activity, or smoking are not permitted for at least 8 to 12 hours prior to testing. A greater than fourfold elevation of plasma metanephrines is highly suggestive of the presence of the tumor. Tumors may occur in sites other than the adrenal (e.g., organs of Zuckerkandl). Computed tomography (CT), magnetic resonance imaging (MRI), or functional imaging techniques are helpful in localization.

THYROID DISEASE

HYPOTHYROIDISM

Epidemiology

Hypothyroidism is a common disorder with an estimated prevalence of 0.4% to 1.2% in the United States. Approximately 40% of cases are overt, with 60% being subclinical. Congenital hypothyroidism due to maternal iodine deficiency or dysgenesis of the thyroid occurs in 1:3,000 to 1:4,000 births.

Pathobiology

The most common causes of hypothyroidism are autoimmune destruction and thyroidectomy or radioablation of the gland. Thyroid hormone is important in early growth and development, and the neurologic consequences of hypothyroidism depend on the age when the deficiency begins. Severe thyroid deficiency in utero or early life results in delayed physical and mental development (cretinism) or myxedema in adults. Thyroid hormone affects neurofilament gene expression, mitochondrial protein synthesis, and the appearance and distribution of laminin, which provides guidance to migrating neurons. Hypothyroidism is associated with pathologic changes in muscle, including accumulation of glycogen and lipids, abnormal and increased mitochondria, dilated sarcoplasmic reticulum, and focal myofibrillar degeneration. The biochemical changes produced in the brain or muscle induced by hypothyroidism are still not well correlated with clinical symptomatology.

Clinical Features

Only gold members can continue reading. Log In or Register to continue