• Hyponatremia
• Hypernatremia
• Hypoglycemia
• Nonketotic hyperglycemia
• Hypocalcemia
• Hypomagnesemia

Hyponatremia is relatively common in hospitalized patients. It occurs when an imbalance between the intake and excretion of water results in excess water relative to sodium. This imbalance may be the consequence of impaired water excretion or fluid intake that exceeds the excretory capacity of the kidneys (as in primary polydipsia6 or iatrogenic administration7).

Water excretion may be deficient because of renal dysfunction, or it may be inhibited by the persistent release of ADH induced by volume depletion or the secretion of inappropriate ADH. The syndrome of inappropriate secretion of antidiuretic hormone (SIADH) has many possible causes:8,9

• Malignant neoplasia
• Carcinoma: bronchogenic, pancreatic, duodenal, ureteral, prostatic, bladder
• Lymphoma and leukemia
• Thymoma and mesothelioma
• Central nervous system disorders
• Trauma
• Infection
• Tumors
• Porphyria
• Pulmonary disorders
• Tuberculosis
• Pneumonia
• Fungal infections
• Lung abscesses
• Ventilators with positive pressure
• Drugs
• Desmopressin
• Oxytocin
• Vincristine
• Chlorpropamide
• Nicotine
• Cyclophosphamide
• Morphine
• Amitriptyline
• Selective serotonin reuptake inhibitors (SSRIs)

Hyponatremia may also be seen in cerebral or renal salt-wasting conditions. Sodium depletion from the kidneys is associated with adrenal insufficiency (Addison’s disease) and the use of thiazide diuretics. Extrarenal sodium loss occurs with vomiting, diarrhea, or third-spacing. Other causes of hyponatremia are hypothyroidism, hyperlipidemia and hyperproteinemia (in which serum osmolality is normal), and hyperglycemia (in which the serum is hyperosmolar).

Clinical presentation

Because acute hyponatremia causes plasma osmolality to fall, water moves into cells to maintain osmotic equilibrium between the extracellular and intracellular fluid. In the brain, water entry into neurons results in cerebral edema. Consequently, the symptoms of acute hyponatremia are predominantly neurological and parallel the severity of cerebral edema.10

Symptoms include:11,12

• nausea and malaise (earliest symptoms)
• headache
• confusion
• lethargy
• obtundation
• muscle twitching
• seizures (partial or generalized tonic-clonic)

In one retrospective series, hyponatremia was the cause of seizures in 70% of infants younger than 6 months who lacked other findings suggesting a cause.13

Coma and respiratory arrest may occur if the plasma sodium concentration rapidly falls below 115 to 120 meq/L.14 The associated mortality rate can be over 50%10 and survivors risk permanent neurological damage.

Evaluation

The diagnostic evaluation of hyponatremia requires a search for causes of water retention, sodium loss, or both. Besides serum sodium concentration, other key laboratory studies are the plasma osmolality, the urine osmolality, and the urine sodium concentration. If plasma osmolality is low, the urine osmolality can be used to distinguish between impaired water excretion (inappropriately high urine osmolality) and primary polydipsia (appropriately low urine osmolality). SIADH is confirmed by inappropriately elevated urine osmolality (often above 300 mOsm/kg) and urine sodium concentration (usually above 40 mEq/liter).

Other tests that may be indicated are plasma creatinine concentration to evaluate for renal dysfunction, and assays of adrenal and thyroid function to rule out an endocrinopathy.

Treatment

The treatment of hyponatremia should be guided by the clinical setting. Patients with chronic hyponatremia require no specific therapy other than restricting water intake. Rapid sodium correction in patients with chronic asymptomatic hyponatremia may be hazardous.15 Water restriction to below the level of water output is the primary therapy for chronic hyponatremia associated with:

• heart failure
• cirrhosis
• SIADH
• primary polydipsia
• advanced renal failure

If fluid must be given to patients with SIADH, then the osmolality of the administered fluid must exceed the osmolality of the urine. Otherwise, the hyponatremia may worsen. Consequently, isotonic saline has a limited role in the correction of the hyponatremia, because the urine osmolality in SIADH is usually above 300 mOsm/kg.

Because of the high associated mortality, acute symptomatic hyponatremia represents a medical emergency. Isotonic saline should be administered to patients with true volume depletion, diuretic therapy, or adrenal insufficiency, in which cortisol replacement is also indicated. Although sodium concentrations should generally not be increased faster than 1.5–2.0 mmol/liter per hour or 12 mmol/liter per day,16,17 higher correction rates have been well tolerated in children.18 The risks of fast correction are central pontine and extrapontine myelinolysis, characterized by spastic quadriparesis, pseudobulbar palsy, and an encephalopathy ranging from confusion to coma.15–17,19

Adapted from: Schachter SC and Lopez MR. Metabolic disorders. In: Ettinger AB and Devinsky O, eds. Managing epilepsy and co-existing disorders. Boston: Butterworth-Heinemann; 2002;195–208.
With permission from Elsevier (www.elsevier.com).
List of causes of SIADH - Adapted from: JP Kokko. Fluids and Electrolytes. In L Goldman, JC Bennett (eds), Cecil Textbook of Medicine (21st ed). Philadelphia: Saunders, 2000;540–567

Reviewed and revised April 2004 by Steven C. Schachter, MD, epilepsy.com Editorial Board.

As plasma sodium concentrations rise in healthy subjects, thirst is stimulated and eventually quenched, and ADH is released. Both actions lower the plasma sodium concentration back to normal. Hypernatremia, a relative deficit of water to sodium solute, may occur in patients who do not respond to thirst by drinking fluids. Infants, confused adults, and the elderly are at particularly high risk.20

Other causes of hypernatremia are:

• iatrogenic administration of hypertonic sodium solutions (e.g., sodium bicarbonate)
• solute-free water losses from the urinary tract (e.g., diabetes insipidus, osmotic diuresis)
• solute-free water losses from the gastrointestinal tract (e.g., osmotic diarrhea)
• water losses from the respiratory tract
• hypothalamic lesions that affect thirst or osmoreceptor function
• generalized tonic-clonic seizures

Generalized tonic-clonic seizures, particularly those that result in lactic acidosis, may transiently elevate serum sodium. Intracellular glycogen is metabolized to lactate in muscles during seizures. Intracellular osmolality increases, because lactate is more osmotically active than glycogen. As a result, water moves into cells, causing hypernatremia. Sodium concentrations normalize within 5 to 15 minutes after the cessation of exertion.

Clinical presentation

The rise in plasma sodium concentration and therefore plasma osmolality causes acute water movement out of brain cells. Consequently, the symptoms of hypernatremia are primarily neurologic and are related to the severity of the hypernatremia and the rapidity with which it develops.21 As brain volume decreases, there may be rupture of cerebral veins, focal intracerebral and subarachnoid hemorrhages, and irreversible neuronal damage.21,22 If hypernatremia is untreated, lethargy, weakness, and irritability progress to twitching, seizures, coma, and death, especially with severe hypernatremia.23

Evaluation

The cause of hypernatremia is usually apparent from the history of the patient and can be confirmed by measuring urine osmolality.21 If urine osmolality exceeds 700–800 mOsm/kg, then both hypothalamic and renal function are intact, and the hypernatremia is likely due to incompletely replaced insensible or gastrointestinal fluid losses, sodium overload, or insufficient oral water intake.

These possible causes can be distinguished by measuring the urine sodium concentration:

• If less than 25 mEq/liter, water loss and volume depletion are the primary problems.
• If above 100m Eq/liter, the cause is ingestion or administration of hypertonic sodium solution.24

Plasma osmolality that exceeds urine osmolality is consistent with diabetes insipidus, either central (i.e., ADH is deficient) or nephrogenic (i.e., the kidney resists the action of ADH). The site of the problem can be determined by administering exogenous ADH. If the disorder is central, the urine osmolality rises by 50% or more. If it is nephrogenic, there is no response.21 Nephrogenic diabetes insipidus in adults is associated with chronic lithium use and hypercalcemia.

Treatment

Patients with chronic hypernatremia are generally asymptomatic. Lowering their plasma sodium concentrations too rapidly can be dangerous because of the possibility of inducing cerebral edema.25

In patients with hypernatremia caused by water loss or inadequate fluid intake, 120 mL of free water per hour should be administered orally or intravenously, while carefully monitoring the plasma and urine sodium concentrations, as well as central venous pressure when necessary.23

In patients with diabetes insipidus, the goals of therapy are to decrease the urine output and give specific therapy for the underlying cause.

Adapted from: Schachter SC and Lopez MR. Metabolic disorders. In: Ettinger AB and Devinsky O, eds. Managing epilepsy and co-existing disorders. Boston: Butterworth-Heinemann; 2002;195–208.
With permission from Elsevier (www.elsevier.com).

Reviewed and revised April 2004 by Steven C. Schachter, MD, epilepsy.com Editorial Board.

The generally accepted normal range for fasting plasma glucose is 70–100 mg/dL, so patients with a fasting plasma glucose concentration less than 60 mg/dL may have a hypoglycemic disorder. Symptomatic hypoglycemia is usually associated with concentrations less than 50 mg/dL. The most common cause is an excessive dose of insulin or other hypoglycemic agents.26 In general, the causes of fasting hypoglycemia can be divided into those that involve overutilization of glucose by the body, and those that involve impaired production:

• Overutilization of glucose
• Hyperinsulinis
• Insulinoma
• Exogenous insulin
• Sulfonylureas
• Immune disease with insulin or insulin receptor antibodies
• Drugs (e.g., quinine, disopyramide, pentamidine)
• Sepsis
• Appropriate insulin levels
• Extrapancreatic tumors
• Systemic carnitine deficiency
• Deficiency in enzymes of fat oxidation
• 3-Hydroxy-3-methylglutaryl-CoA lyase deficiency
• Cachexia with fat depletion
• Impaired production of glucose
• Hormone deficiencies
• Hypopituitarism
• Adrenal insufficiency
• Catecholamine deficiency
• Glucagon deficiency
• Enzyme defects
• Glucose-6-phosphatase
• Liver phosphorylase
• Pyruvate carboxylase
• Phosphoenolpyruvate carboxykinase
• Fructose-1,6-bisphosphatase
• Glycogen synthetase
• Substrate deficiency
• Ketotic hypoglycemia of infancy
• Severe malnutrition, muscle wasting
• Late pregnancy
• Liver disease
• Hepatic congestion
• Severe hepatitis
• Cirrhosis
• Uremia
• Hypothermia
• Drugs
• Alcohol
• Propranolol
• Salicylates

Clinical presentation

The clinical manifestations of hypoglycemia parallel the rate of decline in serum glucose concentration, more so than the absolute glucose concentration.

Early symptoms may include

• sweating
• sensation of warmth
• fatigue
• headache
• anxiety
• nausea
• visual disturbances
• dizziness
• hunger
• tremor

Few patients have every symptom.

Later findings are confusion, drowsiness, delirium, seizures, and coma. Seizures are usually generalized, although partial seizures may occur.27 Lateralized weakness, even in the absence of a structural brain lesion, may be seen.

Evaluation

Symptomatic hypoglycemia should be suspected when patients under treatment for diabetes have a change in mental status or new-onset seizures. To confirm the diagnosis, serum glucose concentrations ideally should be measured when patients are symptomatic.28 Further evaluation usually discloses the underlying cause.29 An electroencephalogram (EEG) while patients are symptomatic from hypoglycemia may show background slowing with or without epileptiform features.

Treatment

Early or mild symptoms resolve with oral sugar. Patients presenting with altered mental status or seizures should be treated with intravenous glucose once blood samples have been drawn.

Diabetic patients with recurrent symptomatic hypoglycemia require modification in their treatment regimen and instruction on the use of oral glucose to prevent the onset or worsening of hypoglycemic symptoms.

Adapted from: Schachter SC and Lopez MR. Metabolic disorders. In: Ettinger AB and Devinsky O, eds. Managing epilepsy and co-existing disorders. Boston: Butterworth-Heinemann; 2002;195–208.
With permission from Elsevier (www.elsevier.com).
List of Causes - Adapted from: DW Foster, AH Rubenstein. Hypoglycemia. In AS Fauci, E Braunwald, KJ Isselbacher, et al. (eds), Harrison’s Principles of Internal Medicine (14th ed). New York: McGraw-Hill, 1998;2081–2087.

Reviewed and revised April 2004 by Steven C. Schachter, MD, epilepsy.com Editorial Board.

Neurologic signs are common, and include:31,32

• focal seizures
• epilepsia partialis continua
• myoclonus
• opsoclonia
• hemiparesis
• increased motor tone
• impaired consciousness

Focal seizures may present variably from patient to patient. Stereotypic tonic changes in body posture and speech arrest, associated with supplementary motor area seizures, have been well described.33 The syndrome of transient focal reflex epilepsy and neurologic deficits in elderly patients is highly suggestive of NKH.34

Relatively late symptoms are reduced consciousness and cessation of seizures as hyperglycemia and hyperosmolality worsen.35

Epilepsia partialis continua (EPC) can be an early symptom and persist in association with the presence of hyponatremia.35 The pathogenesis of EPC is thought to require metabolic disturbances including hyperglycemia, mild hyperosmolality, hyponatremia, lack of ketoacidosis, and an area of pre-existing focal cerebral damage.35

Evaluation

In addition to plasma glucose concentrations that typically exceed 1,000 mg/dL, NKH is characterized by hyperosmolality and dehydration from hyperglycemia-induced osmotic diuresis.30 Unlike diabetic ketoacidosis, there is no ketoacid accumulation.

Laboratory findings confirm the hyperglycemia and hyperosmolality and may also demonstrate a mild metabolic acidosis, as well as hypokalemia, hyponatremia, and elevations of blood urea nitrogen and creatinine.

Treatment

The mortality rate is more than 50%, typically from circulatory collapse, and therefore NKH represents a medical emergency. Treatment consists of insulin, correction of electrolyte abnormalities, and reversal of the hyperosmolality with rehydration. (The average fluid deficit is 10 liters.)

Focal seizures are often resistant to antiepileptic drugs but do respond to insulin and restoration of circulatory volume.36,37

Adapted from: Schachter SC and Lopez MR. Metabolic disorders. In: Ettinger AB and Devinsky O, eds. Managing epilepsy and co-existing disorders. Boston: Butterworth-Heinemann; 2002;195–208. With permission from Elsevier (www.elsevier.com).

Reviewed and revised April 2004 by Steven C. Schachter, MD, epilepsy.com Editorial Board.

Hypocalcemia is a common finding in intensive care units, particularly among patients with pancreatitis, hypomagnesemia, and septic shock.38,39 It is also a frequent finding in the intensive care nursery, because neonatal hypocalcemia is usually associated with premature or difficult birth or perinatal asphyxia. It may also occur in newborns of mothers with diabetes or hyperparathyroidism or in small-for-gestational-age newborns.

Clinical presentation

The symptoms of hypocalcemia generally reflect the degree of hypocalcemia and the acuteness of the fall in serum ionized calcium concentration. Even slowly developing hypocalcemia may produce an encephalopathy, dementia, depression, or psychosis, however.

Acute hypocalcemia primarily causes neurologic symptoms because of increased neuromuscular excitability. Symptoms include:

• numbness and tingling of the fingers, toes, and circumoral region
• muscle cramping, stiffness
• carpopedal spasm, tetany (flexor spasms in the arms and extensor spasms in the legs)
• laryngeal stridor
• tremor and chorea (may be misdiagnosed as seizures)
• seizures

Hypocalcemic newborns may present with hypotonia, apnea, poor feeding, jitteriness, or seizures.

Seizures may or may not occur in conjunction with tetany. Types are generalized tonic-clonic, focal motor, and less frequently, atypical absence and akinetic seizures.3,40,41 They occur in 20-25% of patients presenting with hypocalcemia as a medical emergency42 and in 30-70% of patients with symptomatic hypoparathyroidism, usually in conjunction with tetany, altered mental status, and hypocalcemia.3

Tetany, which may be mistaken for motor seizures, results from spontaneous action potentials originating in peripheral nerves when the serum ionized calcium concentration falls below 4.3 mg/dL (usually corresponding to a total serum calcium concentration of 7.0-7.5 mg/dL). Tetany can also be induced by respiratory alkalosis, hypomagnesemia, and hypokalemia.43

Evaluation

The examination shows mental status changes, including irritability, depression, and psychosis. Papilledema may be present, as may Trousseau's and Chvostek's signs.

Trousseau's sign — carpal spasm due to regional ischemia to the hand — may be observed by inflating a blood pressure cuff on the upper arm above systolic pressure for 2 to 3 minutes. This sign is present in 6% of healthy persons and is also associated with alkalotic states, hypomagnesemia, hypokalemia, and hyperkalemia.

Chvostek's sign — contraction of the facial muscles, especially the upper lip or nasal alae, elicited by lightly tapping the facial nerve below the zygomatic arch — may also be present in healthy patients and absent in patients with chronic hypocalcemia.

The diagnosis of hypocalcemia should be confirmed by repeated measurement of serum calcium. If the diagnosis of hypocalcemia is uncertain (e.g., if the patient has hypoalbuminemia), serum ionized calcium should be measured for verification.

Other laboratory tests that may establish the underlying cause in selected patients are:

• creatinine
• amylase
• magnesium
• phosphate
• PTH
• calcidiol
• calcitriol

Hyperphosphatemia with normal alkaline phosphatase and renal function are indicative of hypoparathyroidism, which may be confirmed by a low or undetectable PTH concentration. Hyperphosphatemia with elevated creatinine suggests renal failure. Normal or low serum phosphorus should prompt measurement of vitamin D metabolites and assessment of gastrointestinal function to check for vitamin D deficiency and malabsorption. In these situations, PTH levels are elevated because normal parathyroid glands attempt to compensate for hypocalcemia.

The electrocardiogram (ECG) may show prolongation of the Q-T interval, and the EEG may demonstrate slowing and generalized bursts of spikes.44

Treatment

Patients with symptomatic hypocalcemia should be treated immediately because of the high associated morbidity and mortality.39 Intravenous calcium is the most appropriate treatment, unless severe hypomagnesemia is present. Ten to 20 mL of 10% calcium gluconate (containing 10 mg of elemental calcium per mL) should be administered over 10 to 20 minutes. Calcium should not be given more rapidly because of the risk of serious cardiac dysfunction, including systolic arrest. (Patients taking cardiac glycosides are at particularly high risk.)

In less urgent settings, slow IV infusion (over 4-8 hours) of 20 mg/kg of elemental calcium may be given.

Hypomagnesemia is a common cause of hypocalcemia, because it can both induce resistance to PTH and diminish its secretion.39,45-47 Thus, if seizures continue despite adequate therapy with calcium replacement, hypomagnesemia should be investigated as the possible cause of the hypocalcemia and should be treated appropriately.

An infusion raises the serum calcium concentration for up to 3 hours, so additional slow infusions of calcium are usually necessary. The dose should be 0.5-1.5 mg/kg per hour. Either 10% calcium gluconate (90 mg of elemental calcium per 10-mL ampule) or 10% calcium chloride (360 mg per 10-mL ampule) can be used. The calcium should be diluted in dextrose and water or saline, because concentrated calcium solutions are irritating to veins. Calcium gluconate is less likely to cause tissue necrosis, if extravasated, than calcium chloride. Intramuscular injection of calcium gluconate is contraindicated because it can cause local necrosis.

Intravenous calcium should be continued until the patient is able to take an effective regimen of oral calcium and vitamin D. Calcitriol, in a dose of 0.25-0.50 mg per day, is the preferred preparation of vitamin D for patients with severe acute hypocalcemia, because of its rapid onset of action. Patients with hypoparathyroidism require chronic vitamin D and calcium therapy.40

Adapted from: Schachter SC and Lopez MR. Metabolic disorders. In: Ettinger AB and Devinsky O, eds. Managing epilepsy and co-existing disorders. Boston: Butterworth-Heinemann; 2002;195?208. With permission from Elsevier (www.elsevier.com).

Reviewed and revised April 2004 by Steven C. Schachter, MD, epilepsy.com Editorial Board.

Hypomagnesemia is defined as magnesium concentration less than 1.6 mEq/liter (<1.9 mg/dL). Its causes are of three types:48,49

(1) Inadequate dietary intake

(2) Diminished gastrointestinal absorption

• disorders or bypass of the small bowel (e.g., prolonged parenteral feeding, especially in combination with loss of body fluids via gastric suction or diarrhea)
• diarrhea
• malabsorption
• steatorrhea
• acute pancreatitis

(3) Wasting from the kidneys50

• inhibition of sodium reabsorption in those segments in which magnesium transport passively follows that of sodium
• primary defect in renal tubular magnesium reabsorption
• alcohol-induced tubular dysfunction
• use of drugs that promote magnesium wasting from the kidneys:
• loop and thiazide diuretics
• aminoglycoside antibiotics
• amphotericin B
• cisplatin
• pentamidine
• cyclosporine

In neonates, hypomagnesemia is associated with prematurity, DiGeorge syndrome, familial hypoparathyroidism, and exchange transfusions. It may also occur in infants of diabetic mothers or mothers with hyperparathyroidism or magnesium deficiency.

The overall frequency of hypomagnesemia in hospitalized patients is 11%,51 although this may be an underestimate.52 The frequency may be as high as 65% in patients in an intensive care setting, in whom major operations, poor nutrition, diuretics, hypoalbuminemia, and aminoglycosides may be factors.49,53,54

Clinical presentation

Magnesium, an essential cation, is involved in many enzymatic reactions and is a cofactor to adenosine triphosphatase. Consequently, magnesium is critical in energy-requiring metabolic processes.49

Symptoms of hypomagnesemia include:

• irritability
• agitation
• confusion
• anorexia
• nausea
• vomiting
• lethargy
• weakness
• tetany (correlates with the secondary development of hypocalcemia or hypokalemia)
• tremor
• muscle fasciculations

Seizures, usually tonic-clonic, can occur in neonates and adults in association with severe hypomagnesemia.10

Evaluation

Physical examination may reveal an abnormal mental status and a positive Trousseau's sign, carpal spasm due to regional ischemia to the hand. Trousseau's sign may be observed by inflating a blood pressure cuff on the upper arm above systolic pressure for 2 to 3 minutes. (This sign is present in 6% of healthy persons and is also associated with alkalotic states, hypocalcemia, hypokalemia, and hyperkalemia.)

Once hypomagnesemia is confirmed by measurement of the serum magnesium level, the etiology can usually be obtained from the history. If there is no apparent cause, the distinction between GI and renal losses can be made by measuring 24-hour urinary magnesium excretion or the fractional excretion of magnesium on a random urine specimen.

Other electrolyte disturbances may be found. For example, hypokalemia occurs in 40-60% of patients with hypomagnesemia,52,54 and hypocalcemia and metabolic alkalosis are frequent findings.

Electrocardiogram (ECG) changes, including widening of the QRS wave complex and peaking of T waves, may be seen.

Treatment

Treatment with magnesium salts (e.g., sulfate or chloride) should be given for symptomatic hypomagnesemia. In the setting of seizures, 2-4 g of magnesium sulfate heptahydrate may be given intravenously (as a 10% solution in 20 to 30 mL of 5% dextrose in water) over 5 to 15 minutes and repeated, if seizures persist, to a total of 10 g over the next 6 hours.

During magnesium replacement, calcium gluconate should be available, because apnea from respiratory muscle paralysis can result from transient hypermagnesemia.

In neonates, 0.25-1.00 mL of 50% magnesium sulfate heptahydrate (0.125-0.500 g) can be injected intramuscularly or given intravenously over 10 to 15 minutes with careful ECG monitoring. This dose may be repeated two to three times a day.

Besides magnesium replacement, the underlying disease should also be corrected when possible.

Adapted from: Schachter SC and Lopez MR. Metabolic disorders. In: Ettinger AB and Devinsky O, eds. Managing epilepsy and co-existing disorders. Boston: Butterworth-Heinemann; 2002;195?208.
With permission from Elsevier (www.elsevier.com).

Reviewed and revised April 2004 by Steven C. Schachter, MD, epilepsy.com Editorial Board.