Metabolic Disorders : Epilepsy.com/Professionals

Although all patients with epilepsy have seizures, the converse is not necessarily true, particularly for patients with seizures from metabolic disturbances.

Metabolic disorders cause seizures in three ways:1–3

alteration of intracellular osmolality
depletion of substrates essential for cellular metabolism or membrane function
intracellular accumulation of toxic substances

With the exception of certain inborn errors of metabolism, most acute metabolic derangements that present with seizures are treatable and reversible with specific interventions. Seizures due to metabolic disorders present diagnostic as well as therapeutic challenges, however. Close collaboration between the neurologist and the medical specialist is essential in the care of the patient with seizures of metabolic origin.

Because AEDs alone are generally of limited benefit, and acute metabolic derangements can be fatal if untreated, neurologists must consider this group of disorders when patients present with new-onset seizures or when patients with epilepsy have an unexplained worsening of seizure frequency or severity.95

Other areas of epilepsy.com/professionals cover seizures due to Renal disorders and Hepatic disorders (See Liver Disease).

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

Electrolyte abnormalities

Author: SC Schachter and MR Lopez

Acute electrolyte disorders that cause seizures typically present with rapidly progressive neurologic symptoms and signs, and therefore require emergency treatment. In general, the short-term prognosis for seizure control and neurologic recovery is related to the correction of the specific metabolic derangements; the long-term prognosis depends on correction of the underlying condition.

Water homeostasis and disorders of electrolytes, particularly sodium, are interrelated. Intracellular fluid (ICF) and extracellular fluid (ECF) are the two components of total body water.4 The ECF is further divided into the intravascular compartment (plasma water) and the extravascular compartment (interstitial water).

The concentrations of particles (osmoles) in the ECF and ICF determine their osmolalities, expressed in milliosmoles (mOsm) per kilogram water. Because water moves along osmolality gradients and can pass freely across cell membranes, the osmolality of each compartment of the ECF equilibrates. Secondarily, the osmolality of the ECF equilibrates with the ICF. Because the ECF compartment has a considerably larger volume than the ICF compartment, ECF osmolality determines the volume of ICF once osmotic equilibrium is achieved.

Although water freely passes across cell membranes, some solutes may not because of active transporters or pumps that maintain different solute concentrations between the inside and outside of cells. These solutes determine the effective osmolality (also referred to as tonicity) of the compartment in which they are concentrated. Sodium is mainly confined to the ECF and hence largely determines the effective osmolality of the ECF (and, in turn, the ICF volume). Consequently, the main cause of serum hypoosmolality is hyponatremia.

The normal range of plasma osmolality is 275–290 mOsm/kg, which is maintained as long as the volume of water absorbed equals the volume of water excreted. Water excretion occurs predominantly through the kidneys but also through insensible water loss (e.g., sweat, respiration) and stool. Renal water excretion is regulated by antidiuretic hormone (ADH; also called arginine vasopressin), which acts on the kidney to reabsorb water. The secretion of ADH from the posterior pituitary in healthy subjects depends on serum osmolality or tonicity, which is sensed by hypothalamic osmoreceptors as a function of cell volume.5

In healthy subjects, a water load causes plasma osmolality to fall. The release of ADH is suppressed, resulting in the rapid excretion of water from the kidneys as dilute urine. Conversely, circulatory volume loss, such as through bleeding, vomiting, diarrhea, and use of diuretics, or in association with edematous states (e.g., nephrotic syndrome, congestive heart failure) elevates ADH secretion. Absorption of water from the kidneys is increased and the urine becomes concentrated.4

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

Hyponatremia

Author: SC Schachter and MR Lopez

Causes

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 polydipsia 6 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.

Hypernatremia

Author: SC Schachter and MR Lopez

Causes

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.

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

Hypoglycemia

Author: SC Schachter and MR Lopez

Causes

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.

Nonketotic hyperglycemia

Clinical presentation

Older patients with type 2 diabetes are most likely to present with nonketotic hyperglycemia (NKH). Precipitating factors include infection, surgery, dialysis, tube feedings, and stress.

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

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

Hypocalcemia

Causes

Calcium homeostasis is maintained by vitamin D and parathyroid hormone (PTH), and the major causes of hypocalcemia are vitamin D deficiency and hypoparathyroidism.

The main dietary sources of vitamin D are fatty fish and fortified foods, such as milk. Vitamin D is also synthesized from 7-dehydrocholesterol in skin, when exposed to ultraviolet light. The liver metabolizes vitamin D to calcidiol (25-hydroxyvitamin D), which is then converted to calcitriol (1,25-dihydroxyvitamin D) in the kidney by a process stimulated by PTH and hypophosphatemia and inhibited by calcium and phosphate. Vitamin D deficiency can result from:

poor dietary intake
intestinal malabsorption
decreased hepatic production of calcidiol
increased hepatic metabolism of calcidiol to inactive metabolites (a process stimulated by enzyme-inducing antiepileptic drugs)
decreased renal production of calcitriol in patients with kidney failure

As plasma calcium concentration falls, PTH secretion increases, resulting in increased calcium release from bone (a process dependent on calcitriol) and enhanced renal production of calcitriol, which in turn increases calcium absorption in the gut and feeds back and inhibits further PTH secretion.

The ionized (free) calcium fraction, not protein-bound calcium, affects the excitability of muscle cells and neurons. The normal serum concentration of ionized calcium is 4.0-5.2 mg/dL, which represents slightly less than half of total serum calcium concentration. Symptomatic hypocalcemia is usually defined as an abnormal reduction in the serum ionized calcium concentration, or as a serum calcium level less than 7.5 mg/dL in the presence of normal levels of serum proteins. (The total serum calcium concentration is reduced approximately 0.8 mg/dL for every 1 g/dL reduction in serum albumin concentration.) Occasionally, symptomatic hypocalcemia can occur with normal total serum calcium concentration. For example, acute respiratory alkalosis causes increased protein binding of ionized calcium.

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

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

Hypomagnesemia

Author: SC Schachter and MR Lopez

Causes

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.

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

Hypoparathyroidism

Author: SC Schachter and MR Lopez

Causes

The differential diagnosis of hypoparathyroidism includes:

(1) idiopathic hypoparathyroidism, in which the parathyroids are absent or atrophied. This condition occurs sporadically or in association with genetic autoimmune syndromes or DiGeorge syndrome.

(2) pseudohypoparathyroidism, in which bone and kidney tissue are unresponsive to parathyroid hormone (PTH)

(3) damage or accidental removal of parathyroid glands during thyroidectomy. Transient hypoparathyroidism and hypocalcemia from subtotal thyroidectomy are common,55,56 but permanent hypoparathyroidism is a rare complication of thyroid surgery.

Clinical presentation

Seizures occur in up to 70% of patients with symptomatic hypoparathyroidism.3,41,57

Parkinsonism, dystonia, hemiballismus, choreoathetosis, and oculogyric crises occur in 5–10% of patients with idiopathic hypoparathyroidism,58 but are less common in patients with surgical hypoparathyroidism or other causes of hypocalcemia.59 Other neurologic findings may include spastic paraplegia, ataxia, dysarthria, and dysphagia.

Chronic hypocalcemia in patients with hypoparathyroidism may be associated with dry, puffy, or coarse skin; dental changes (if hypocalcemia is present during early development60,61); and cataracts.

Evaluation

PTH levels are low or undetectable in patients with hypoparathyroidism.

In pseudohypoparathyroidism, patients have hypocalcemia. Most have high serum PTH and phosphate concentrations and low serum calcitriol concentrations. Brain CT scans may show basal ganglia calcification, particularly in chronic cases.62,63

Treatment

The acute management of symptomatic hypoparathyroidism involves correction of hypocalcemia and other associated electrolyte abnormalities.

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

Hyperthyroidism

Causes

Common causes of hyperthyroidism are Graves' disease, toxic multinodular goiter, toxic adenoma, and subacute thyroiditis.

Clinical presentation

The clinical presentation is the same regardless of underlying cause. Symptoms include anxiety, nervousness, emotional lability, sweating, heat insensitivity, palpitations, fatigue, weight loss, irregular or fast heartbeat, muscle wasting and weakness, and increased bowel movements.64 Signs include tachycardia, warm and moist skin, enhanced physiologic tremor, lid retraction and lag, rapid speech, hyperactivity, and proximal muscle weakness. Chorea may be seen,65 and a goiter may be present, depending on the cause. Exophthalmos is present only in patients with Graves' disease.

In patients with established epilepsy (including generalized epilepsy syndromes), seizures and paroxysmal EEG abnormalities can be exacerbated by hyperthyroidism.66,67 In other patients, focal or generalized seizures occur only during thyrotoxic episodes.68 Seizure exacerbations usually remit when patients become euthyroid with treatment.

Evaluation

The diagnosis is confirmed by low serum thyroid-stimulating hormone (TSH) and high concentrations of T4, T3, or both.

The electrocardiogram (ECG) often shows atrial fibrillation.

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

Adrenal insufficiency

Author: SC Schachter and MR Lopez

Clinical presentation

The clinical presentation of adrenal insufficiency varies, depending on the degree of adrenal dysfunction, the acuteness with which function is lost, the extent of mineralocorticoid production, and the magnitude of superimposed stress or medical illness.

Common symptoms of adrenal insufficiency are:

generalized weakness
malaise
easy fatigue
loss of appetite
weight loss

Seizures can occur in association with hyponatremia. They are treated by correcting serum sodium and glucose concentrations.

An adrenal crisis may result from infection or other stress superimposed on adrenal insufficiency or from bilateral adrenal infarction or hemorrhage. The usual presenting clinical picture is shock. Nausea, vomiting, abdominal pain, confusion, or coma may occur as well.

Patients with chronic primary adrenal insufficiency have hyperpigmented skin, especially in areas exposed to sun or contact pressure. Other possible findings include mood instability, psychotic ideation, and an encephalopathy varying from inattention to delirium and stupor.

SIADH due to cortisol deficiency and volume loss due to mineralocorticoid deficiency causes hyponatremia in 85-90% of patients. Hyperkalemia, hyperchloremic acidosis, and hypoglycemia may be present.

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

Inborn errors

Author: SC Schachter and MR Lopez

Inborn errors of metabolism are rare, genetically transmitted enzyme deficiencies that block or interfere with cellular metabolic pathways. In British Columbia, from 1969 to 1996, the incidence was approximately 40 cases per 100,000 live births, including diseases of amino acids, organic acids, the urea cycle, galactosemia, primary lactic acidoses, glycogen storage, and lysosomal storage and diseases specifically involving peroxisomal and mitochondrial respiratory chain dysfunction.69

Symptoms and signs occur when pathway intermediates proximal to the enzymatic block accumulate to toxic levels, or they result from deficient products of the affected metabolic pathways. Most inborn errors of metabolism present with progressive neurologic and systemic symptoms. Seizures often begin in the neonatal period or during infancy. See Table: Metabolic Disorders of Infantile Seizures for a list of metabolic disorders associated with infantile seizures.

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

Phenylketonuria

Author: SC Schachter and MR Lopez

Pathophysiology

Phenylketonuria (PKU), an aminoaciduria, is characterized by an absence or severe deficiency of phenylalanine hydroxylase, the enzyme that hydroxylates phenylalanine to tyrosine. PKU is inherited as an autosomal recessive trait. Variant forms caused by other enzyme defects have been identified.

Normal diets typically contain more than twice the amount of phenylalanine (an essential amino acid) needed for protein synthesis. Excess phenylalanine is converted to tyrosine. In the absence of phenylalanine hydroxylase, plasma phenylalanine concentrations are elevated, and phenylalanine is excreted in the urine. Some excess phenylalanine is metabolized to phenylacetic acid, as well as other acids, and excreted in the urine and sweat.

Clinical presentation

Serum phenylalanine concentrations in infants with PKU are normal at birth but begin to rise within the first few weeks of life. Excessive phenylalanine is generally thought responsible for the brain damage that underlies the severe mental retardation and seizure disorder of PKU. In untreated infants, cognitive delay becomes evident within 6 months and is progressive. The majority of affected children are unable to talk, and a significant proportion never learns to walk.

Characteristic physical findings include:

light hair, eye, and skin pigmentation
an eczematous rash
hyperactive behavior
a musty or mousy odor (due to phenylacetic acid in the sweat)

Approximately 25% of patients have generalized or partial seizures. Infantile spasms and myoclonic seizures may occur.70 On the EEG, all patients have slowing, epileptiform discharges, or hypsarrhythmic patterns.71

Evaluation

Because newborns with PKU usually seem healthy, the diagnosis requires screening tests, which are mandated by law. Confirmatory tests are high plasma phenylalanine and normal or low plasma tyrosine concentrations.

Treatment

Treatment consists of dietary restriction of phenylalanine. The goal is to provide necessary but not excessive amounts of phenylalanine, typically 250 to 500 mg per day. The diet should be instituted immediately after birth and maintained throughout life to preserve cognitive and neuropsychologic function. Monitoring of plasma phenylalanine levels is required to gauge compliance and adequacy of the prescribed diet.

Antiepileptic drugs are given when necessary.

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

Niemann-Pick disease

Author: SC Schachter and MR Lopez

Pathophysiology

Niemann-Pick disease is an autosomal-recessive lipidosis in which sphingomyelin (i.e., ceramide phosphorylcholine) accumulates in the lysosomes of reticuloendothelial cells.72 Several types have been identified. Types A and B result from a deficiency of acid sphingomyelinase. Types C and D are characterized by abnormal cholesterol esterification and transport out of the lysosome.

Clinical presentation

Type C is most associated with seizures. Two subtypes of type-C Niemann-Pick disease have been identified based on the temporal sequence of neurologic events, neurophysiologic abnormalities, and longevity.73

Neonates with type-C Niemann-Pick disease may be jaundiced at birth. Slowly progressive neurologic deterioration begins within 2 years. Partial, generalized tonic-clonic and atonic seizures may occur and are usually refractory to antiepileptic drugs.73 Hepatosplenomegaly is often present.

Evaluation

Laboratory testing may show pancytopenia from bone marrow infiltration. Sphingomyelinase activity is not reduced, but the cholesterol transport defect can be documented in cell culture.

Treatment

There is currently no specific treatment for any of the Niemann-Pick disease subtypes, and care is supportive.72

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

Gaucher's disease

Author: SC Schachter and MR Lopez

Pathophysiology

Gaucher's disease is an autosomal-recessive lipidosis caused by a deficiency of acid b-glucosidase.72 Because acid b-glucosidase hydrolyzes glucocerebroside in lysosomes to glucose and ceramide, Gaucher's disease is characterized by the lysosomal accumulation of glucocerebrosides (primarily glucosylceramide).

Clinical presentation

There are three subtypes of Gaucher's disease. Types II and III involve the CNS. Patients with type II die in infancy, but type III, the juvenile form, may present in infancy or childhood.

Glucocerebroside accumulates in cells of the liver, spleen, lymph nodes, and bone marrow, leading to organomegaly, lymphadenopathy, and skeletal pain. Neurologic signs include ataxic gait, cognitive dysfunction, and partial and generalized tonic-clonic seizures.

Evaluation

The diagnosis is confirmed by the presence of characteristic cells on bone marrow aspiration and the lack of acid b-glucosidase activity in cell culture.

Treatment

There is no known effective treatment for the neurologic involvement in type III Gaucher’s disease.

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

Mucopolysaccharidoses

Author: SC Schachter and MR Lopez

Pathophysiology

The mucopolysaccharidoses are lysosomal storage disorders due to a lack of enzymes that normally degrade glycosaminoglycans. They are characterized by the intracellular accumulation and urinary excretion of glycosaminoglycans (i.e., mucopolysaccharides). The seven types of mucopolysaccharidoses are each distinguished by an excess of a particular urinary mucopolysaccharide.74

Clinical presentation

Inheritance is autosomal dominant, except for type II, which is x-linked.

Clinical features vary but generally include a characteristic coarse facies (i.e., thickened lips and open mouth), short height, bony abnormalities, mental retardation, corneal opacities, and hepatosplenomegaly.

Type III (Sanfilippo's syndrome) is the most common mucopolysaccharidosis. It has four subtypes. The onset of symptoms is usually after 2 years of age, followed by rapidly progressive neurologic and cognitive deterioration. Seizures occur in nearly half of patients.

Evaluation

The EEG shows nonspecific abnormalities, and neuroimaging studies reveal cortical atrophy and ventricular dilatation.

Laboratory studies confirm abnormalities on urine screening tests for glycosaminoglycans. Sophisticated cell culture or serum assays are available to evaluate patients for specific enzyme deficiencies.

Treatment

Treatment is symptomatic. Enzyme replacement by bone marrow transplantation has produced systemic improvement in selected patients but has not prevented neurologic deterioration.

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

Hepatic porphyria

Author: SC Schachter and MR Lopez

Pathophysiology

The porphyrias are caused by inherited deficiencies of enzymes involved in heme synthesis.75 Heme is used in the bone marrow to make hemoglobin and in the liver to make cytochrome P-450 enzymes. The hepatic synthesis of heme is largely regulated by d-aminolevulinic acid (ALA) synthase, an inducible enzyme.

The symptoms and signs of the porphyrias result from the accumulation of toxic metabolites. They are classified either as erythropoietic and hepatic or on the basis of the specific enzyme deficiency.

Seizures and other neurologic manifestations only occur in the hepatic group, in which the porphyrin precursors ALA and porphobilinogen (PBG) accumulate.76 Both compounds have been implicated as directly neurotoxic.77

Three acute hepatic porphyrias, all autosomal dominant, are associated with seizures:78

acute intermittent porphyria (AIP)
hereditary coproporphyria (HCP)
variegate porphyria (VP)

HCP and VP are much less common than AIP. They present similarly except that HCP and VP are also associated with cutaneous photosensitivity.

Patients with AIP have approximately 50% reduction of PBG deaminase activity.75 This condition is particularly prevalent in Northern Europe, especially Finland.79 When the demand for hepatic heme synthesis is increased, the reduced PBG deaminase activity leads to the accumulation of ALA and PBG in the liver, plasma, and urine.78 Some of the PBG and ALA is converted to porphyrin.

AIP can be precipitated by:80

drugs that induce hepatic ALA synthase (e.g., enzyme-inducing antiepileptic drugs)
drugs that inhibit PBG deaminase (e.g., sulfonamide antibiotics)
hormones (e.g., estrogen, progesterone and its metabolites, and oral contraceptives)
alcohol
reduced caloric intake
intercurrent infections
major surgery

Clinical presentation

Clinical manifestations can persist for days to weeks and may be preceded by nonspecific symptoms.76 The most common acute symptom is abdominal pain, often severe enough to require narcotic analgesia. The pain is sometimes accompanied by nausea, vomiting, ileus, and constipation.

Sympathetically mediated signs include tachycardia, hypertension, sweating, and tremors. Sleep disturbance, anxiety, delirium, hallucinations, depressed mood, and paranoid delusions may be present.81,82 Lethargy and coma occur rarely. Peripheral motor neuropathies may lead to foot or wrist drops.

Seizures associated with AIP occur either as a direct neurologic manifestation of the condition or from hyponatremia, which may result from SIADH, vomiting, diarrhea, or poor oral intake. Some studies suggest that focal and generalized seizures occur in nearly one-third of pediatric cases and up to 20% of adult cases.83-85 By contrast, a study of patients registered at the National Porphyria Center in Sweden found that the lifetime prevalence of AIP-associated seizures was 2.2% of all those with known AIP and 5.1% of all those with manifest AIP.86

Evaluation

The diagnosis may be suspected based on the clinical presentation and may be confirmed by the presence of photosensitive porphyrins in the urine and reduced monopyrrole PBG deaminase in red blood cells.81,87

Treatment

After a definitive diagnosis, treatment of acute attacks consists of

narcotic analgesia for pain (see below)
symptomatic therapy of nausea, anxiety, and restlessness
oral or intravenous glucose
Intravenous hematin or heme arginate (to reverse the induction of ALA synthase and thereby reduce the production and accumulation of ALA and PBG78,88,89)

Drugs known to precipitate AIP must be avoided,78,90 particularly when treating seizures, pain, and acute anxiety attacks. Hahn et al. used a cell-culture model of primary chicken embryo liver cells, which maintain intact heme synthesis and regulation, to study the effects of several of the more recently approved antiepileptic drugs on porphyrin accumulation.91 Based on the results, they recommended vigabatrin or gabapentin, for which success was reported anecdotally,92 but not felbamate, lamotrigine, or tiagabine, as possible treatments for seizures in patients with porphyria.

Similar animal studies have suggested that patients with acute porphyrias may be at greater risk for developing porphyric attacks when treated with certain medications:

Greater risk	Less risk
tramadol	hydrocodone, oxycodone, morphine93
bupropion, nefazodone	fluoxetine, paroxetine
diazepam, midazolam, triazolam	low doses of lorazepam, oxazepam94