Introduction
Patients frequently consult a physician because of alarming “spells.” These may consist of symptoms such as sudden malaise, a feeling of faintness, flushing, a perceptibly irregular or rapid heart beat, dizziness, sweating, confusion, as well as myriad other alarming complaints. The physician’s task is to differentiate psychological from organic complaints and potentially dangerous from benign symptoms and to localize the symptoms to a particular system of the body—cerebrovascular, neurologic, endocrine, or other. When patients are seen with lip smacking, loss of consciousness, prolonged jerking movements, and tongue biting, the diagnosis of a tonic–clonic seizure is straightforward. More difficult diagnostic problems occur when the complaints are subjective, as with symptoms of autonomic or sensory origin, because objective confirmation of disease may be lacking, and the subjective perceptions (e.g., feelings of dissociation, anxiety, or panic) are often difficult to put into words.
Among the many entities considered in the differential diagnosis of “spells” are those associated with metabolic and endocrine disturbances, some of which have proved to be among the “great imitators” of other diseases, including hysteria. Endocrine or metabolic disturbances may in themselves cause seizures, or they may exacerbate epilepsies by lowering seizure thresholds. The primary emphasis of this chapter is on metabolic and endocrine disturbances that result in symptoms that may be mistaken for seizures.
General Comments Regarding Patient History
Spells associated with many endocrine disturbances are characteristically accompanied by other features of the endocrine disease. For example, patients with spells caused by thyrotoxicosis usually have tremulousness, weight loss, and sweating in addition to palpitations and anxiety attacks. In other endocrine or metabolic disturbances, however, few clinical signs may be present. In such cases, attention must be paid to the particular precipitating factors, pattern, course, duration, and resolution of the spell in the context of the patient’s medical history. For example, in a patient who has undergone gastric surgery, the malaise, sweating, and light-headedness occurring at fixed intervals after meals should alert the physician to the possibility of reactive hypoglycemia with “dumping syndrome.” Similarly, patients with diabetes who are taking oral hypoglycemic agents or insulin may have the same symptomatology resulting from episodic hypoglycemia. Typical settings would be a lower-than-usual caloric intake, or unanticipated exercise without appropriate changes in insulin. In these cases, symptomatic hypoglycemia may supervene over the ensuing hours. Conversely, hyperglycemia may appear with intercurrent illness and decreased insulin dosage.
Particular inquiry into dietary habits, medications, and prior medical problems or surgery, therefore, is essential in making the appropriate diagnosis.
With some diseases, the constellation of signs and symptoms may provide the physician with a diagnosis through “pattern recognition.” For example, intermittent severe abdominal pain and episodes of limb paralysis, delirium, and “port wine”–colored urine are typical features of an acute intermittent porphyric crisis. A history of previous similar attacks, possibly triggered by drugs, should be sought. In a similar vein, the simultaneous occurrence of paroxysmal headache, facial flushing, and hypertension will evoke the diagnosis of pheochromocytoma.
Specific Metabolic and Endocrine Disorders
Hypoglycemia
Because the central nervous system requires a constant supply of glucose, hypoglycemia may produce transient neurologic dysfunction51 that can be mistaken for or even precipitate seizures. When delivery of glucose to the central nervous system is insufficient, a number of signs and symptoms may appear (Table 1). The particular array of clinical features may vary with the rapidity of development of hypoglycemia and the depth of hypoglycemia, as may the degree of impairment and level of consciousness. The symptoms of hypoglycemia are generally divided into adrenergic symptoms and neuroglycopenic symptoms. The former include anxiety, nervousness, palpitations, diaphoresis, and tremors. Neuroglycopenic symptoms include lethargy, disorientation, confusion, blurry vision, stupor, and in severe cases seizures and coma. In rare cases, focal weakness may also be seen.
Table 1 Symptoms of hypoglycemia in insulin-dependent diabetes mellitus | ||||||||||||||||
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Table 2 Causes of hypoglycemia | ||
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The symptoms of falling levels of blood glucose usually occur episodically, and the diagnosis rests on demonstrating subnormal levels of blood sugar in the symptomatic patient. Some patients may lose the warning symptoms17 and adapt to the sensations that accompany hypoglycemia. This is known as “hypoglycemia unawareness.” Patients particularly at risk are the elderly,70 those taking adrenergic blocking agents,47 and patients who have a history of frequent hypoglycemic attacks. The variability in the threshold at which particular patients experience symptoms is marked. Normal individuals when fasting may have a blood glucose concentration that falls below 45 mg/dL and remain asymptomatic; in contrast, some patients who have insulin-dependent diabetes mellitus and certain elderly patients become symptomatic when blood glucose
levels descend toward 45 mg/dL.50,51 Diagnosis of symptomatic hypoglycemia, therefore, lies in determining a low plasma glucose level in the symptomatic patient, with relief effected when blood glucose concentrations are normalized (Whipple’s triad).73 It is important to appreciate that some poorly controlled diabetics (who have marked hyperglycemia) experience hypoglycemic symptoms (mostly adrenergic symptoms) even when their glucose levels are lowered toward normal. It is interesting that with better glycemic control, these symptoms resolve.
levels descend toward 45 mg/dL.50,51 Diagnosis of symptomatic hypoglycemia, therefore, lies in determining a low plasma glucose level in the symptomatic patient, with relief effected when blood glucose concentrations are normalized (Whipple’s triad).73 It is important to appreciate that some poorly controlled diabetics (who have marked hyperglycemia) experience hypoglycemic symptoms (mostly adrenergic symptoms) even when their glucose levels are lowered toward normal. It is interesting that with better glycemic control, these symptoms resolve.
Causes of Hypoglycemia
The differential diagnosis of hypoglycemia includes the array of causes leading to the condition (Table 2). Because plasma glucose concentrations are affected by a number of agents, imbalance in these dynamic forces may cause hypoglycemia. In humans, there is a dynamic and often delicate balance between factors that increase blood glucose levels, such as epinephrine, cortisol, growth hormone, and glucagon, and factors that decrease glucose levels, including oral hypoglycemic agents, exogenous or endogenous insulin, and concurrent he- patic or renal disease. An excess of glucose-lowering agents or insufficiency of gluconeogenic mechanisms may result in symptomatic hypoglycemia. Common causes are oral hypoglycemic agents, excess exogenous or endogenous insulin, he- patic or renal disease, heavy alcohol use, a decrease in food intake, or unanticipated exercise in an insulin-dependent diabetic patient.45 A number of drugs when taken concurrently may enhance or prolong the hypoglycemic effect of oral hypoglycemic agents or inhibit compensatory mechanisms of hepatic glucose release.2 These include anticoagulants, beta-blockers, clofibrate, isoniazid, phenylbutazone, salicylates, and sulfonamides. Other drugs may precipitate hypoglycemia, including colchicine, disopyramide, haloperidol, paracetamol, pentamidine, perhexiline, and quinine. Insulin-treated patients may have hypoglycemic attacks as a result of missed meals, excess insulin dose, and exercise not compensated for by an increase in food intake or adjustment in insulin dose.
Of the oral hypoglycemic agents, the sulfonylureas are the most notorious in causing hypoglycemia. The elderly and the patients with renal disease are particularly sensitive to sulfonylurea-induced hypoglycemia (due to decreased clearance of the drug). They are also the most common cause of factitious hypoglycemia. This surreptitious use is most commonly seen in medical personnel and persons with family members on these agents.15
Excessive long-term alcohol intake, resulting in chronic disease of the liver, also predisposes to hypoglycemia because glycogen stores are depleted.42 Similarly, patients who have not eaten for several days and who have a binge of moderate to heavy drinking may also experience transient or even prolonged hypoglycemia up to 1 day after the end of the binge.
Hypoglycemia may occur in patients after gastric surgery, later than the symptoms of “dumping syndrome.” Overactivity of the “enteroinsular axis” is thought to result in excessive release of glucose-dependent insulinotropic peptide (GIP) and other hormones, which in turn increase insulin secretion after ingestion of glucose.66
Other rare causes of hypoglycemia include endogenous hyperinsulinism caused by insulin-secreting tumors (insulinomas) of the pancreas.34 Of such tumors, 10% are malignant, 10% are of questionable malignancy, and the rest are benign.53 Patients with multiple endocrine neoplasia type I may have multiple tumors that secrete a variety of hormones, including pancreatic polypeptide, glucagon, gastrin, and somatostatin. Symptoms typically include blurred vision, double vision, sweating, palpitations, weakness, confusion, behavioral changes, obtundation, and tonic–clonic seizures. Patients with adrenal insufficiency and growth hormone deficiency may also present with hypoglycemia. Finally, tumor (nonislet)-induced hypoglycemia is seen in rare retroperitoneal mesenchymal tumors that elaborate insulin-like growth factor II (IGF-II). Surgical resection is the treatment of choice in these patients.
Diagnostic Investigation
When the diagnosis of symptomatic hypoglycemia has been made, determination of the particular cause depends largely on the medical and surgical history, evaluation of medications that are known to impair glucose regulation, and a physical examination.
In insulin-treated patients, the query is directed at the dose, timing, method, and location of subcutaneous administration (e.g., thigh, which has greater absorption, especially if the patient exercises). A frequent cause of inappropriate dosing is self-administration of insulin by patients with impaired vision. Syringes with larger writing are now available. Attention should
also be directed at patients taking oral hypoglycemic agents or other newly introduced drugs that may interfere with glucose regulation. Surreptitious injection of insulin may be deduced by a high plasma insulin level with a low plasma C-peptide concentration. This contrasts with excessive endogenous insulin production, in which a high plasma insulin level is accompanied by an appropriately high C-peptide level. Both sulfo- nylureas and insulinomas result in elevated levels of plasma insulin and C-peptide levels. Hence, measurement of serum levels of sulfonylureas is an important part of the workup of hypoglycemia. If insulinoma is suspected, endoscopic ultrasound, magnetic resonance imaging of the abdomen, and arteriography are the main imaging modalities. Octreotide scan is not very sensitive. Percutaneous transhepatic portal venous sampling may be needed in some cases.
also be directed at patients taking oral hypoglycemic agents or other newly introduced drugs that may interfere with glucose regulation. Surreptitious injection of insulin may be deduced by a high plasma insulin level with a low plasma C-peptide concentration. This contrasts with excessive endogenous insulin production, in which a high plasma insulin level is accompanied by an appropriately high C-peptide level. Both sulfo- nylureas and insulinomas result in elevated levels of plasma insulin and C-peptide levels. Hence, measurement of serum levels of sulfonylureas is an important part of the workup of hypoglycemia. If insulinoma is suspected, endoscopic ultrasound, magnetic resonance imaging of the abdomen, and arteriography are the main imaging modalities. Octreotide scan is not very sensitive. Percutaneous transhepatic portal venous sampling may be needed in some cases.
Treatment
Treatment of episodic hypoglycemia is based on treatment of the underlying cause. In patients treated with insulin and hypoglycemic agents, careful attention to modification of the regimen may prevent hypoglycemic dips. The aid of a specialist in diabetes should be sought. After gastric surgery, “dumping syndrome” may be avoided by more frequent and smaller meals containing complex carbohydrates. Insulin-secreting tumors are usually resected; if they are inoperable, octreotide, a long-acting somatostatin analog, may be used. If hypoglycemia is a manifestation of adrenal insufficiency, physiologic glucocorticoid replacement results in the resolution of hypoglycemia.
Association with Epileptic Seizures
Hypoglycemia itself may be the cause of seizures. In infants, these usually occur on the second postnatal day in newborns who are small for gestational age. Occasionally, hypoglycemia may be seen in infants of diabetic mothers and in cases of syndromes associated with defects of gluconeogenesis, defects of organic or amino acid metabolism, and mitochondrial dysfunction. Hypoglycemia may trigger tonic–clonic seizures and cause paroxysmal electroencephalographic (EEG) activity that can be confused with seizure activity.
Hyperglycemia
Hyperglycemia is a state that develops gradually, typically during a period of days to weeks. Because changes are gradual and usually progressive, these events are not often mistaken for an epileptic disturbance. Hyperglycemia in the absence of ketosis, however, may be associated with a number of abnormal movements, including asterixis, paroxysmal choreoathetosis, hemiplegia, and partial epileptic seizures.38,56 Such partial seizures are typically motor, often exhibit a jacksonian march, and may be reflex seizures or effort induced. The seizures are resistant to antiepileptic drugs, but they usually regress on treatment of the hyperglycemia within a few hours to a few days.7 Occasionally, partial seizures may continue for long periods in the state of epilepsia partialis continua.22,56 Ketotic hyperglycemia is much less frequently associated with seizures, possibly because of the antiepileptic effect of ketosis.
Hypocalcemia
The predominant clinical features of hypocalcemia are the consequence of a decrease in ionized serum calcium, which in turn leads to an increase in neuromuscular excitability. This may be accompanied by numbness and tingling in the fingers, paresthesias, stiffness, muscle cramps, carpopedal spasm, and perioral numbness. Associated clinical features include papilledema, cataracts, developmental defects, and mental retardation in the congenital forms of the disease and calcification of the basal ganglia with dyskinesias. The electrocardiogram may show prolonged QTc intervals and T-wave changes.
Several conditions may be accompanied by hypocalcemia, each with its own constellation of clinical features. Well-described causes include thyroid and parathyroid surgery, chronic renal failure, renal tubular acidosis, malabsorption, hypomagnesemia, blood transfusion, acute pancreatitis, osteomalacia or rickets, vitamin D deficiency, intake of chelating agents, and pseudohypoparathyroidism.
Bedside diagnostic features include the Chvostek sign (twitching of the lips or nasal alae, or even of the entire half of the face, produced by tapping the branches of the facial nerve as it passes through the parotid gland above the angle of the jaw). The diagnostic indicator is a low level of ionized serum calcium. The underlying cause of hypocalcemia should be sought.
Tetany is characterized by flexor spasms in the arms and extensor spasms in the legs; it may resemble tonic–clonic seizures and can be induced by hyperventilation. Both tetany and partial or tonic–clonic seizures may supervene.18 Tonic–clonic seizures can be treated by administering a slow intravenous infusion of 15 mL of 10% calcium gluconate under cardiac monitoring.
Hypercalcemia
The most common cause of hypercalcemia is primary hyperparathyroidism. In this condition, hypercalcemia is generally mild and typically develops over a period of months to years; in most cases, patients are asymptomatic. In contrast, malignancy-induced hypercalcemia usually develops rapidly and can be severe and is accompanied variably by anorexia, nausea, vomiting, weight loss, and constipation. Neurologic symptoms are general fatigue, muscular weakness, and proximal myopathy, with mental status changes that include personality changes, depression, stupor, coma, and tonic–clonic seizures. The major causes of hypercalcemia are primary or tertiary hyperparathyroidism, humoral hypercalcemia of malignancy, multiple myeloma, paraneoplastic disorders, bone metastases, thyrotoxicosis, milk-alkali syndrome, vitamin D intoxication, immobilization, and rarely Paget disease of bone. Adrenal insufficiency and acromegaly are other rare endocrine causes of hypercalcemia.
Occasionally, a more acute hypercalcemia is characterized by paroxysmal headache, nausea, vomiting, abdominal pain, and constipation. Muscle weakness, lethargy, and coma may supervene. There may be visual impairment, tonic–clonic seizures, and spike-and-wave discharges over the occipital regions.26
The diagnosis of hypercalcemia is based on the finding of a raised level of ionized calcium. The next step is to measure serum levels of intact parathyroid hormone (iPTH). This test is fundamental to differentiating between parathyroid and nonparathyroid causes of hypercalcemia. An electrocardiogram may show a shortened QTc duration.
The underlying cause should be sought and treated. Acute management of hypercalcemia includes hydration with saline, subcutaneous calcitonin, and intravenous bisphosphonates.
Excess of Growth Hormone
Paroxysmal attacks of sweating that occur with excess levels of growth hormone may be mistaken for autonomic seizures.25 Sweating occurs due to increased concentration of sweat glands as a result of growth hormone excess. In contrast to autonomic
seizures, paroxysms are not associated with other ictal manifestations.
seizures, paroxysms are not associated with other ictal manifestations.
Hyperthyroidism
The acute malaise, anxiety, sweating, tremulousness, and tachycardia of hyperthyroidism may mimic partial seizures,52 as may choreiform movements and encephalopathy.1,24 Features of the illness that suggest thyrotoxicosis include heat intolerance, weight loss despite a healthy appetite, hyperdefecation, goiter, exophthalmos, palpitations, atrial fibrillation, and muscle wasting and weakness. Proximal myopathy is the classical presentation of Graves disease. Patients with severe thyrotoxicosis (thyroid storm) may present with fever, stupor or coma, pyramidal and bulbar dysfunction, and convulsions.31,41 It is important to appreciate that many elderly patients may not have any of the typical clinical features of hyperthyroidism (apathetic hyperthyroidism). Cardiac arrhythmias, like atrial fibrillation, may be the initial presentation in these subjects.
The most common causes of hyperthyroidism include Graves disease, solitary toxic adenoma, and toxic multinodular goiter (Plummer disease) Other etiologies of thyrotoxicosis include iodine-induced thyrotoxicosis, various thyroiditides, factitious thyrotoxicosis, and central hyperthyroidism (TSHomas). Large metastases of follicular thyroid cancer are a rare cause of thyrotoxicosis. The diagnosis is based on finding an undetectable or suppressed thyroid-stimulating hormone (TSH and increased T3 or free T4 levels. Imaging with radioactive iodine is the gold standard in determining the etiology of thyrotoxicosis.
Occasionally, choreiform movements and encephalopathies occur. Clinical seizures may rarely supervene, and partial motor, adversive, and tonic–clonic seizures are reported. A rare manifestation of hyperthyroidism is hypokalemic periodic paralysis, which may be confused with a seizure. This entity is predominantly seen in individuals of Asian decent, and Graves disease is the most common underlying etiology. The attacks may last for minutes to hours. Ingestion of a carbohydrate meal is a well-known trigger (the release of insulin being responsible for shifts in potassium).
Hypothyroidism
Hashimoto thyroiditis is the most common cause of primary hypothyroidism. Other causes include history of thyroid surgery, neck radiation, lithium therapy, and central hypothyroidism. General symptoms include dry skin, constipation, cold intolerance, sallow skin discoloration, ovulatory dysfunction, and minimal weight gain. Hypothyroidism may be accompanied by neurologic complaints, including neuropathy, myopathy, choreoathetosis, dementia, or even coma.10,37,57 Sudden falls from arrhythmias secondary to hypothyroidism rarely occur.40 There may be nocturnal jerking movements from obstructive sleep apnea and, more rarely, central sleep apnea. Comatose, hypothyroid patients may have tonic–clonic seizures. In severe hypothyroidism, patients may develop psychosis with hallucinations (myxedema madness). Myxedema coma remains the dreaded complication of severe hypothyroidism. It usually occurs in the elderly and has a high mortality rate. Intravenous thyroxine therapy is indicated in these cases.
Diagnosis rests on finding elevated TSH and low T3 or free T4 levels in cases of primary hypothyroidism. In secondary hypothyroidism due to pituitary dysfunction, TSH levels are low or inappropriately normal. Imaging of the pituitary with magnetic resonance imaging (MRI) is mandatory in such cases to rule out mass lesions. Treatment involves replacement of thyroid hormone.
Hashimoto Encephalopathy
Very few entities in neurology and endocrinology have puzzled and at the same time fascinated clinicians (more neurologists than endocrinologists). Hashimoto encephalopathy is one such entity. The story began in 1966 when Lord Brain, a famous English neurologist, described a case of a man with confusion, disorientation, and seizures.6 The patient also had transient episodes of fluctuating hemiparesis of different extremities and aphasia, which completely resolved. Investigations revealed abnormalities in EEG, and cerebrospinal fluid (CSF) showed elevated levels of protein. Brain antibodies were not detected in the serum. This patient had known Hashimoto thyroiditis with positive antithyroid antibodies and was on optimal thyroxine therapy during these episodes. According to Lord Brain, “the apparent onset of Hashimoto’s disease—was followed by an extraordinary and puzzling neurological illness which waxed and waned for over a year.” He concluded, “antibody studies in future cases of unexplained encephalopathy should show whether we have described a syndrome or a coincidence.”
Hashimoto encephalopathy remains a diagnosis of exclusion, which is usually entertained by a neurologist when a case of acute or subacute encephalopathy is seen in a patient with no evidence of other etiologies (infectious and metabolic causes excluded), positive antithyroid antibodies, and good clinical response to steroids. It is important, however, to appreciate that positive antithyroid antibodies are present in 10% of the U.S. population.23 Hence, it is debatable whether Hashimoto encephalopathy is a distinct clinical entity or a coincidence of a rare encephalopathy that occurs in an individual with a common endocrinologic condition and a not uncommon circulating antibody. Furthermore, there is no evidence that antithyroid antibodies are directly responsible for the encephalopathy. As a result, some have suggested that this entity should be called “steroid-responsive encephalopathy associated with Hashimoto thyroiditis.”
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