Pathogenesis and Pathophysiology. The adrenal gland is the effector organ of the hypothalamic-pituitary-adrenal (HPA) axis and secretes cortisol in response to stimulation by pituitary-derived corticotropin (adrenocorticotropic hormone [ACTH]). Pituitary function, in turn, is under the control of corticotropin-releasing hormone from the hypothalamus. Dysfunction anywhere in the HPA axis may result in adrenal insufficiency. Primary adrenal insufficiency (PAI), is due to bilateral adrenal gland destruction and secondary adrenal insufficiency (SAI) results from hypothalamic or pituitary dysfunction. The most frequent cause of adrenal insufficiency is iatrogenic SAI following the withdrawal of exogenously administered steroids.
The fatigue and weakness associated with hypoadrenalism reflect the associated hypotension as well as the water and electrolyte disturbances. The role of glucocorticoids in catabolic energy mobilization likely also contributes.
Epidemiology and Risk Factors. PAI is relatively rare, may occur at any age, and affects both sexes equally. yj Acquired immunodeficiency syndrome and active tuberculosis are significant risk factors for PAI. Major risk factors for SAI include prior administration of exogenous corticosteroids, especially prolonged, high-dose courses, and any destructive lesion of the pituitary or hypothalamus.
Clinical Features and Associated Disorders. The clinical features of adrenal insufficiency are influenced by the site of dysfunction, because PAI affects all of the adrenocortical hormones, whereas SAI only affects glucocorticoids. Thus, hyperpigmentation, salt craving, and hyperkalemia are unique to patients with PAI. Patients with adrenal insufficiency may present acutely or as a chronic condition. Acute adrenal insufficiency is a medical emergency (so-called addisonian crisis) characterized by mental status changes, fever, hypotension, volume depletion, arthralgias, myalgias, and abdominal pain that may mimic an acute abdomen. yi Chronic adrenal insufficiency may present more insidiously with fatigue, weakness, GI symptoms, amenorrhea, decreased libido, salt craving, arthralgias, and hypoglycemic symptoms. Neurological manifestations can include confusion, apathy, depression, psychosis, paranoia, and myalgias, as well as hypoglycemic symptoms. In addition, a past medical history of cancer, recent tuberculosis exposure or steroid usage, immunosuppression, a history of treated Cushing's syndrome, features of hypothalamic/ pituitary disease, or other endocrine deficiencies, as well as a family history of a sex-linked recessive disorder, should be sought.
Differential Diagnosis. In the industrialized world, approximately 70 percent of cases of PAI are autoimmune in etiology (due to the polyendocrine deficiency syndrome), 20 percent are related to tuberculosis (most common cause
worldwide), and the remaining 10 percent are due to other causes (. TabJ.e..,3.8.-.9 )  SAI commonly follows exogenous steroid withdrawal and the surgical treatment of Cushing's syndrome; it is uncommonly related to hypothalamic or pituitary lesions. yi The neurological differential diagnosis relates to the rapidity of onset of the hypoadrenalism. In the setting of acute adrenal insufficiency (i.e., addisonian crisis), the differential diagnosis of acute onset encephalopathy must be entertained in addition to those disorders that produce septic shock. With a more chronic presentation, the differential diagnosis varies with the clinical manifestations and includes those disorders associated with encephalopathy, fatigue, weakness, or myalgias.
Evaluation. The evaluation of patients with suspected adrenal insufficiency serves to determine the adequacy of cortisol production and to localize the process within the HPA axis (i.e., PAI versus SAI). Tests to assess cortisol production include the serum cortisol level, ACTH (Cortrosyn) stimulation test, insulin tolerance test, and the metyrapone test. The plasma ACTH level is the principal localizing test, yi and in severely stressed patients with normal adrenal function, serum cortisol levels range from 20 to 120 pg/dl.y] In unstressed patients, the normal cortisol level overlaps with that observed in patients with adrenal insufficiency, making random cortisol testing less useful in this group.
Management. In patients receiving exogenous glucocorticoids, the prevention of HPA axis suppression is aided by using the lowest possible dosage, shortest duration, and an every-other-day dosing schedule, when possible. The treatment of adrenal insufficiency is hormone replacement. In general, in acute adrenal insufficiency, IV hydrocortisone is administered and fluid, Na, and glucose are replaced. In chronic adrenal insufficiency, the preferred replacement glucocorticoid is also hydrocortisone, because it has a short half-life, and is therefore less likely to produce Cushing's syndrome or osteoporosis. W A typical regimen is hydrocortisone, 20 mg in the morning and 10 mg in the evening. Mineralocorticoid replacement may be required in PAI and is usually provided by fludrocortisone (Florinef), 0.05 to 0.1 mg/day, along with the recommendation for a high Na diet.
TABLE 38-9 -- MAJOR CAUSES OF ADRENAL INSUFFICIENCY
Primary adrenal insufficiency
Infections Hemorrhage Metastatic disease Drugs Infiltrative
Adrenoleukodystrophy, adrenomyeloneuropathy; congenital adrenal hypoplasia
Secondary adrenal insufficiency
Suppression of the hypothalamic-pituitary-adrenal axis
Modified from Lonaux DL: Adrenocortical insufficiency. In Becker KL, Bilezikian JP, Brenner WJ, et al (ed): Principles and Practice of Endocrinology and Metabolism, 2nd ed, Philadelphia, J.B. Lippincott, 1995, pp 682-686; and Rone JK: Adrenal insufficiency In Rakel RE (ed): Saunders Manual of Medical Praetice, Philadelphia, WB. Saunders. l996i, pp 653-656
Hyperadrenalism refers to hypersecretory disorders of the adrenal medulla (e.g., pheochromocytoma) and cortex (e.g., aldosteronism and Cushing's syndrome). Pheochromocytomas are catecholamine-secreting tumors of neural crest (neuroectoderm) origin that may be sporadic or familial. In adults, approximately 10 percent of these tumors are malignant, 10 percent are extra-adrenal (i.e., 90 percent occur within the adrenal glands), and 10 percent are bilateral. 
The major clinical features of pheochromocytoma are headaches, palpitations, diaphoresis, hypertension, hypotension, pallor, weight loss, chest pain, and abdominal pain.yi Other features include dizziness, anxiety, nausea, vomiting, diarrhea, mydriasis, tachycardia, pulmonary edema, and CHF. y A more serious neurological feature is intracranial hemorrhage. Pheochromocytoma multisystem crisis is a serious and rare presentation that is characterized by encephalopathic features, multiple organ failure, fever, and labile blood pressure.  Pheochromocytoma can be associated with multiple endocrine neoplasia (MEN) type II, neurofibromatosis, and von Hippel-Lindau disease. y
The differential diagnosis of hypertension associated with hyperadrenergic symptoms is extensive and includes thyrotoxicosis, anxiety and panic disorders, hypoglycemia, diencephalic epilepsy, acute myocardial infarction, abrupt clonidine withdrawal, and drug usage (e.g., monoamine oxidase inhibitors, cocaine, decongestants). Although pheochromocytoma is rare, its life-threatening status requires consideration and exclusion whenever hypertension is associated with suggestive symptoms, especially the triad of headache, palpitations, and diaphoresis.
A total plasma catecholamine (epinephrine plus norepinephrine) level, drawn 30 minutes after supine rest, can be diagnostic. Values above 2000 pg/ml are pathognomonic for pheochromocytoma, whereas those below 1000 pg/ml exclude pheochromocytoma. Twenty-four-hour urine studies (metanephrines, normetanephrines, and vanillylmandelic acid) and clonidine suppression testing are required when values between these levels are obtained. yi Twenty-four-hour urine studies are diagnostic in up to 90 percent of patients with pheochromocytoma. y Once the diagnosis of pheochromocytoma is confirmed, tumor localization becomes the priority and is best evaluated by abdominal CT.
For neurologists, it is important to consider pheochromocytomas in patients with headaches and other suggestive symptoms. Serious morbidity and mortality may occur when these patients present with headache and beta-blocker therapy is begun, which allows unopposed alpha adrenergic stimulation. This may result in CHF, myocardial or cerebral infarction, malignant hypertension, or death. When pheochromocytoma is considered to be a diagnostic possibility, referral to an endocrinologist for further evaluation and treatment is appropriate. With the widespread availability of imaging (CT, MRI) and biochemical assays, the incidence of undiagnosed pheochromocytoma has dropped significantly.  With surgery, most pheochromocytomas are cured. However, 10 percent are malignant and current treatments for widespread metastases are unsatisfactory.
Aldosteronism results from the overproduction of aldosterone
by the adrenal cortex and can be primary or secondary. Primary aldosteronism refers to aldosteronism related to adrenal gland disorders such as aldosterone-secreting adrenal adenomas (Conn's syndrome) and functional overactivity of both adrenal glands (idiopathic hyperaldosteronism). Secondary aldosteronism refers to stimulation of aldosterone production by extra-adrenal influences, such as occurs in CHF, cirrhosis, volume depletion (or other conditions of decreased effective renal perfusion), and Barrter's syndrome, a rare disorder characterized by hyperreninemia, hypokalemia, and normal blood pressure. Aldosteronism, both primary and secondary, results in hypokalemia and metabolic alkalosis, which, in turn, may cause neurological symptoms. Primary aldosteronism is approximately twice as common in women, occurs between the ages of 30 and 50 years, and is found in approximately 1 percent of hypertensive patients. [1oq] It is the most common endocrine cause of secondary hypertension.
Aldosteronism-induced hypokalemia may trigger episodic attacks of severe muscular weakness (similar to periodic paralysis), tetany, paresthesias, polyuria, and hypertension.^] The episodic attacks of weakness are similar to both the familial and thyrotoxic forms of periodic paralysis, although respiratory paralysis is more common.^ Unlike the familial form, hypokalemia and alkalosis may be present between attacks. y In addition to episodic weakness, a subacute or chronic myopathy may develop. In this setting, serum creatinine kinase may be moderately elevated and EMG examination discloses myopathic features that are often accompanied by fibrillation potentials. y Rarely, rhabdomyolysis and myoglobinuria occur. Laboratory features include an inability to concentrate the urine, hypernatremia, hypokalemia, metabolic alkalosis, and hypokalemic-induced EKG changes. The plasma renin activity should be measured, because this factor allows the differentiation between primary (suppressed) and secondary (elevated) aldosteronism.
The etiology dictates the treatment. In idiopathic hyperaldosteronism, medical therapy is primary, whereas hyperaldosteronism due to an adenoma is typically treated by surgical excision, although medical treatment with spironolactone (an aldosterone antagonist) and dietary Na restriction may be effective (antihypertensives may also be required).
Cushing's syndrome is the clinical expression of chronic excess adrenal corticosteroids (i.e., hypercortisolism) and can be classified into ACTH-dependent and ACTH-independent etiologies. [wi Disorders belonging to the ACTH-dependent category overproduce cortisol in response to excessive ACTH release, whereas those in the ACTH-independent category produce cortisol without ACTH stimulation. ACTH-dependent causes account for 80 percent of the cases of endogenous Cushing's syndrome, and include ACTH-producing pituitary tumors (Cushing's disease; 65 percent), as well as both ACTH-producing (15 percent) and corticotropin-releasing hormone-producing (rare) ectopic tissue. y&i ACTH-independent etiologies account for 20 percent of the cases of Cushing's syndrome, and include adenoma and carcinoma of the adrenal gland, nodular hyperplasia, and cortisol-secreting tumors.  In addition to these endogenous etiologies, prolonged administration of exogenous glucocorticoids can cause a nearly identical syndrome.
The clinical features of Cushing's syndrome vary with the underlying etiology and are dependent on the amount of ACTH, cortisol, and other adrenocortical steroids secreted (...Tab!e...„38-.1Q ). Neuropsychiatry manifestations can include irritability, emotional lability, depression, and psychotic episodes. y , y Approximately 50 percent of the patients with Cushing's disease have muscle weakness. y Other possible neurological signs are mental status changes and visual field defects as well as optic neuropathy when pituitary adenomas extend beyond the confines of the sella turcica. Rarely, the accumulation of fat epidurally can result in the development of a myelopathy. An association with idiopathic intracranial hypertension has also been reported (see Chapter.5,3. ).
Cushing's syndrome must be differentiated from disorders producing secondary hypercortisolism (e.g., obesity, major depression, alcoholism). Initial evaluation usually includes an overnight dexamethasone suppression test and a 24-hour urine collection for free cortisol. Free cortisol typically exceeds 90 pg/day in Cushing's syndrome. The overnight dexamethasone suppression test assesses the patient's ability to suppress cortisol production in response to a low dose of dexamethasone. Typically, 1 mg of dexamethasone is administered at 11 PM, and a blood sample for serum cortisol is drawn at 8 AM. Serum cortisol is suppressed to below 5 pg/dl in normal individuals, whereas it is above 10 pg/dl in patients with Cushing's syndrome. False-positive results may be noted with physiological stress, estrogen or antiepileptic drug use, RF, and endogenous depression. 
Basic laboratory studies may identify glucose intolerance, leukocytosis with lymphopenia, polycythemia, and hypokalemia. Hypokalemia is unusual in Cushing's disease (10 percent) but is much more common in the ectopic ACTH syndrome (60 percent).  An MRI scan of the pituitary is the procedure of choice for the identification of pituitary adenomas. Abdominal CT scanning for the presence of an adrenal tumor is indicated in ACTH-independent syndromes.
_TABLE 38-10 -- THE CLINICAL FEATURES OF CUSHING'S SYNDROME AND DISEASE_
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