You are on page 1of 9

Epilepsia, 47(12):1990–1998, 2006

Blackwell Publishing, Inc.

C 2006 International League Against Epilepsy

Critical Review

Electrolytes Disturbances and Seizures

∗ Luis Castilla-Guerra, †Marı́a del Carmen Fernández-Moreno, ‡José Manuel López-Chozas,

and †Ricardo Fernández-Bolaños
∗ Department of Internal Medicine, Hospital de la Merced, Osuna; †Department of Neurology, Hospital de Valme;
and ‡Department of Internal Medicine, Hospital Virgen del Rocio, Seville, Spain

Electrolyte disturbances are frequently encountered the ultrasound test, he drank a copious amount (4–5 L)
in daily clinical practice. The diagnosis of these abnormal- of water. On physical examination, the patient was con-
ities is commonly made from routine laboratory findings, fused and disoriented. The neurologic examination was
and they are not usually of clinical significance. However, unremarkable. His serum electrolyte levels were as fol-
they may sometimes lead to serious complications when lows: sodium, 112 mEq/L; potassium, 3.4 mEql/L; serum
overlooked or not treated appropriately. osmolality, 235 mOsm/kg; and blood glucose, 124 mg/dl.
Electrolyte abnormalities may affect many organs and Emergency computed tomography of the brain was nor-
tissues, including the brain. Most of the clinical manifesta- mal. We diagnosed hyponatremic encephalopathy due to
tions of these derangements are predominantly neurologic water intoxication and treated with intravenous 3% saline
and parallel the severity of neuronal damage. Furthermore, solution. In 48 h, the patient’s serum sodium level in-
these disorders may appear with seizures, or with rapidly creased to 136 mM. He made a full clinical recovery.
progressive neurologic symptoms and signs, and thus re- It is clear that better training in management of elec-
quire emergency treatment (Rose and Post, 2001; Riggs, trolyte imbalances in patients with seizures is needed to
2002). reduce common and serious neurologic morbidity associ-
Acute and/or severe electrolyte imbalances frequently ated with these medical problems.
cause seizures, and these seizures may be the sole present- We give an overview of the clinical aspects of elec-
ing symptom. Seizures are especially common in patients trolyte disturbances associated with seizures, with special
with sodium disorders, hypocalcemia, and hypomagne- regard to the pathophysiologic mechanisms involved and
semia. Successful management of patient seizures begins treatment recommendations.
with the establishment of an accurate diagnosis of the un-
derlying electrolyte disturbance, because rapid identifica-
tion and correction of the disturbance is necessary to con-
trol seizures and prevent permanent brain damage (Kunze,
2002; Riggs, 2002). Electrolyte homeostasis in the central nervous system
(CNS) is essential for brain function. Regulation of ionic
CASE REPORT balance is a critical process involving a complex array of
molecules for moving ions into and out of the brain and
A 61-year-old man was initially seen in the emergency
involving blood–brain barrier function as well as mech-
department with nausea and emesis and, after several min-
anisms in the membranes of both neurons and glia. Al-
utes, tonic–clonic seizures developed. The patient had a
terations in ion gradients across cellular membranes can
previous medical history of benign prostatic hyperplasia,
have direct and indirect effects on neuronal discharge and
and several hours before admission, he came to the radi-
may facilitate epileptiform activities (Scwartzkroin et al.,
ology department to undergo a routine abdominal ultra-
sound examination. To fill his bladder before undertaking
A variety of pathological states or conditions such as de-
hydration or renal failure are associated with substantial
Accepted August 2, 2006. modifications of plasma osmolality and electrolyte bal-
Address correspondence and reprint requests to Dr. L. Castilla-Guerra ance. These conditions may overcome homeostatic brain
at Juan Ramón Jiménez no 5, Castilleja de Guzmán, 41908, Seville,
Spain. E-mail: systems and provoke profound consequences on brain
doi: 10.1111/j.1528-1167.2006.00861.x metabolism and function.


Clinical manifestations of electrolyte disturbances in The correct diagnosis of seizures secondary to elec-
the CNS are variable. In general, they represent functional trolyte abnormalities begins with a complete serum chem-
disturbances of the brain, and, at least in the beginning, istry evaluation, including measurements of electrolytes,
are generally not associated with morphologic changes in especially sodium, calcium, and magnesium. This workup
brain tissue. Because neurologic symptoms of electrolyte should always be part of the initial diagnostic workup
disorders are generally functional rather than structural, in adult patients with a first-time seizures (Browne and
the neurologic manifestations of electrolyte disturbances Holmes, 2001; Oguni, 2004). Such an electrolyte screen is
are typically reversible (Kunze, 2002; Riggs, 2002). How- particularly important in certain patient populations, such
ever, because functional dysfunction such as seizures can as the elderly, in which metabolic disturbances (e.g., hy-
lead to structural alterations, it is important to treat the un- ponatremia or hypoglycemia) are common. Between 15
derlying disturbance before the pathology becomes per- and 30% of acute symptomatic seizures among seniors
manent. occur in the setting of toxic–metabolic causes (LaRoche
Disorders of sodium and osmolality produce CNS and Helmers, 2003). Further, identification and correction
neuronal depression, with encephalopathy as the ma- of electrolyte imbalances leading to seizures are needed
jor clinical manifestation; these disorders can also pro- to reduce morbidity and mortality associated with these
voke CNS neuronal irritability. Similarly, hypercalcemia medical problems. Thus in a review of 375 adult cases
and hypermagnesemia produce CNS neuronal depression of status epilepticus (SE), 10% had a metabolic disor-
with encephalopathy. Conversely, hypocalcemia and hy- der as the primary etiology of their seizure; in this subset
pomagnesemia cause mainly CNS neuronal irritability of patients, mortality was reported to be as high as 40%
with seizures. In contrast, disorders of potassium rarely (DeLorenzo et al., 1992).
produce symptoms in the CNS but may be associated It is important to note that laboratory screening tests,
with muscle weakness as the major clinical manifestation based on the American Academy of Neurology recom-
(Victor and Ropper, 2001; Riggs, 2002) mendations, are not routinely performed in children and
The main features of CNS neuronal depression and en- should be ordered based on individual clinical circum-
cephalopathy are confusion and slight cognitive distur- stances (Hirtz et al., 2000). However, a thorough history
bances. These features may be accompanied by headache, and a comprehensive neurologic and general examina-
lethargy, weakness, tremor, and so on, usually without tion remain the cornerstone of the clinical diagnosis of
signs of focal cerebral disease or a disorder of cranial epilepsy.
nerves (Kunze, 2002; Riggs, 2002). Treatment of seizures secondary to electrolyte imbal-
Electrolyte disorders frequently cause seizures ances is determined by the underlying cause of the distur-
(Table 1). Seizures are common in patients with sodium bance and should be guided by the clinical setting. In most
disorders, hypocalcemia, and hypomagnesemia (Victor cases of electrolyte imbalance, treatment with an anticon-
and Ropper, 2001; Riggs, 2002). In such cases, seizures vulsant (AED) is not necessary as long as the underly-
are usually generalized tonic–clonic, although partial ing disturbance is rectified. Long-term administration of
seizures or other seizure types can occur. In all these AEDs is not necessary (Victor and Ropper, 2001; Kunze,
cases, rapidly evolving electrolyte abnormalities are more 2002; Riggs, 2002). Indeed, AEDs alone are generally in-
likely to cause seizures than are those occurring gradually. effective if the electrolyte disorder persists.
For this reason, it is not possible to assign absolute levels
of electrolyte above or below which seizures are likely to
occur (Victor and Ropper, 2001).
Changes in blood electrolytes may cause diffuse brain
dysfunction, metabolic encephalopathy, and consequently
TABLE 1. Electrolyte abnormality and seizures in clinical EEG abnormalities.
The EEG has been widely used to evaluate metabolic
Frequency in Frequency of encephalopathies since 1937, when Berguer first observed
Electrolyte clinical seizures in acute/ slow brain activity induced by hypoglycemia (Lin, 2005).
abnormality practice severe imbalance
In general, the most prominent feature of the EEG record
Hyponatremia +++ ++ in encephalopathies (if a change occurs) is slowing of the
Hypernatremia ++ ++/+ normal background frequency. A gradual and progressive
Hypocalcemia + ++/+
Hypercalcemia ++ + decline over the course of the disease may be noted if serial
Hypomagnesemia ++ ++/+ EEGs are performed. Disorganization of the record may
Hypokalemia +++ − develop gradually, and reactivity to photic or other types
Hyperkalemia ++ −
of external stimulation may be altered (Kaplan, 2004a).
+++, Frequent; ++, occasional; +, rare; −, absent. EEG evolution generally correlates well with the severity

Epilepsia, Vol. 47, No. 12, 2006


of encephalopathy. However, EEG has little specificity in TABLE 2. Causes of electrolyte disturbances
differentiating etiologies in most encephalopathies. Partic-
Hyponatremia Dilutional hyponatremia (common cause)
ularly in metabolic encephalopathies, common EEG ob- - Impaired capacity for renal water excretion
servations include a varied degree of slowing, assorted - Diuretic agents
mixtures of epileptiform discharges, high incidence of - Adrenal insufficiency
- Hypothyroidism
triphasic waves (TWs), and (as a rule) reversibility af- - Diarrhea
ter treatment of underlying causes (Kaplan, 2004a; Lin, - Congestive heart failure
2005). - Cirrhosis
- Renal failure
The rate of change of electrolyte balance is more impor- - Syndrome of inappropriate secretion of
tant in determining the degree of EEG abnormality than is antidiuretic hormone (SIADH) (can be
the absolute level of a given electrolyte or metabolite. For caused by cancer, some CNS disorders,
some drugs)
instance, EEG changes are usually more severe in uremic Excessive water intake
encephalopathy if acute deterioration of renal function ex- - Water intoxication
ists (Smith, 2005). - Dilute infant formula
Hyponatremia usually produces nonspecific slowing. Hyperglycemia, mannitol
Very low sodium levels may initially produce poste- Hypernatremia Net water loss (common cause)
rior slowing followed by diffuse delta activity corre- - Impaired access to water (commonly seen
in the elderly, in infants, and in confused
lated clinically with papilledema. However, a variety of adults)
other patterns have been described, such as TWs, burst - Diarrhea (commonly seen in infants)
of high-voltage rhythmic delta activity, and central high- - Unreplaced insensible losses (dermal and
voltage 6-Hz to 7-Hz activity with stimulation-induced - Water losses from the urinary tract (via
paroxysms of delta waves. Although periodic lateral- loop diuretics, diabetes insipidus,
ized epileptiform discharges may occur, full seizure ac- osmotic diuresis, intrinsic renal disease)
Hypertonic sodium gain
tivity is very rare (Reddy and Moorthy, 2001; Kaplan, Clinical interventions (e.g., hypertonic sodium
2004a). infusions, hypertonic saline enemas)
Early EEG changes associated with hypocal- Accidental sodium loading
Hypocalcemia Vitamin D deficiency (common cause)
cemia include evolution from alpha through theta - Chronic kidney failure (decreased renal
and delta dominance. Other EEG findings (generalized production of calcitriol)
spikes, sharp-waves burst of delta activity with sharp - Hepatic failure (decreased production of
components). Generalized paroxysmal discharges and - Poor dietary intake
absence SE have also been reported (Kapplan, 2004a). - Antiepileptic drugs (increased hepatic
Neonatal records may show reversible 3- to 4-Hz spike– metabolism of calcidiol)
- Intestinal malabsorption
waves discharges (Kossoff, 2002). No strict correlation PTH deficiency
links serum calcium level to seizure threshold and/or - Hypoparathyroidism (postoperative,
EEG changes in hypocalcemia. idiopathic, Di George syndrome)
- Hypomagnesemia
In hypercalcemia, EEG changes (fast activity and burst Drugs
of delta and theta slowing) appear when calcium lev- - Calcitonin
els reach ∼13 mg/dl. As calcium level increases, in- - Bisphosphonates
creased background slowing (largely frontal), paroxys- Acute pancreatitis, citrated blood in massive
mal theta/delta bursts, and TWs may appear (Juvarra transfusion
et al., 1985; Kaplan, 2004a). Diffuse and more occipital Hypercalcemia Excess PTH (parathyroid hormone) (common
spike–slow-wave complexes may be found, suggesting a - Primary hyperparathyroidism: adenoma,
calcium-mediated vasospastic effect in the posterior cere- hyperplasia)
bral circulation, also noted with very high calcium levels - Tertiary hyperparathyroidism
- Ectopic PTH secretion
(Kaplan, 1998). When calcium is normalized, the EEG Malignant disease (common cause)
usually improves, but only gradually. - Squamous cell cancer, renal cancer,
ovarian cancer, etc. (secretion of
PTH-related protein)
HYPONATREMIA - Multiple myeloma, breast cancer (local
osteolytic hypercalcemia)
Hyponatremia is defined as a decrease in the serum Drugs
sodium concentration to a level <136 mEq/L. - Thiazides
Hyponatremia is reported to be the cause of seizures in Excess action of vitamin D
- Iatrogenic or self-administrated excess
70% of infants younger than 6 months who lacked findings - Sarcoidosis
suggesting another cause (Farrar et al., 1995).
The main causes of hyponatremia are listed in Table 2. Continued.

Epilepsia, Vol. 47, No. 12, 2006


TABLE 2. Continued. strated that other factors influence outcome, including

the age and the gender of the individual (with children
Thyrotoxicosis, Addison disease, renal and menstruant women the most susceptible) (Fraser and
failure, etc. Arieff, 1997; Bhardwaj, 2006). Thus it is estimated that
Hypomagnesemia Inadequate dietary intake (green vegetables, women have a 25-fold increased risk compared with men
fruits, fish, meat, cereal)
Diminished gastrointestinal absorption (com- of death or permanent neurologic damage as a result of the
mon cause) hyponatremia (Reeves et al., 1998). Hypoxia and ischemia
- Diarrhea impair the brain adaptive mechanisms to hyponatremia
- Laxative abuse
- Malabsorption and worsen the cerebral edema. This point is clinically
- Small bowel diseases important, because it also justifies a quick and appropri-
Wasting from the kidneys (common cause) ate treatment of patients’ seizures.
- Alcohol-induced tubular dysfunction
- Drugs: loop and thiazide diuretics, Finally, this process of adaptation by the brain is also
aminoglycosides, cyclosporine, the source of the risk of osmotic demyelination. The cor-
amphotericin B, pentamidine rection of hyponatremia triggers a “de-adaptation” pro-
- Tubular necrosis
- Renal tubular acidosis cess, during which the electrolytes reaccumulate rapidly
Others in the brain cell, but the reentry of organic osmolytes oc-
Cirrhosis, hungry bone syndrome curs much more slowly. Therefore in patients with chronic
hyponatremia, it has been hypothesized that rapid correc-
tion of serum sodium—before a readjustment of intracel-
CNS pathophysiology lular osmolytes concentrations occurs—results in loss of
The major dangers from acute hyponatremia are brain water from neurons and glia; this process carries with it
cell swelling and herniation. Serious symptoms, princi- the danger of provoking osmotic demyelination syndrome
pally neurologic, may become evident when hyponatremia (ODS), associated with pontine and extrapontine demyeli-
approaches 120 mM (Riggs, 2002). Brain adaptive mecha- nation (Reeves et al., 1998; Adrogué and Madias, 2000a;
nisms to changes in osmolality help explain these adverse Riggs, 2002). However, some investigators have demon-
events. When serum sodium decreases, cerebral edema strated that ODS does not depend on the rate of correction
is counteracted initially by an adaptive process known as of hyponatremia alone but also on concurrent insults [e.g.,
the “regulatory volume decrease,” with the displacement alcoholism, anoxic brain injury, or severe liver dysfunc-
of water from the interstitial space to the cerebrospinal tion (Ayus et al., 1992; Bhradwaj, 2006)].
fluid and then to the systemic circulation. This process
is driven by hydrostatic pressure. Subsequently, the brain Hyponatremia and antiepileptic medications
prevents swelling by the extrusion from brain cells of elec- Hyponatremia has been associated with several AEDs,
trolytes. Partial restoration of brain volume occurs within such as carbamazepine (CBZ) and oxcarbazepine (OXC),
∼3 h (rapid adaptation), with the extrusion from brain and occasionally with valproate (VPA) and lamotrigine
cells of these electrolytes: sodium, potassium, and chlo- (LTG) (Grikiniené et al., 2004).
ride. A second cellular adaptation mechanism to osmolal- The frequency of hyponatremia in OXC (a 10-keto
ity changes is the egress from the brain cells of organic analogue of CBZ)-treated patients is even higher than
osmolytes (osmotically active agents), primarily amino in those receiving CBZ (Dong et al., 2005). The preva-
acids, which is almost fully achieved after 48 h (slow lence ranges—from 1.8% to 40% with CBZ and 23%
adaptation) (Gullans and Verbalis, 1993; Bhardwaj, 2006). to 73% with OXC—depends on the patient population
These organic osmolytes, known previously as “idiogenic studied (Dong et al., 2005; Kuz and Manssourian, 2005).
osmoles,” play an important role in this cellular adapta- Several risk factors have been reported to increase the
tion to chronic osmolality changes. If the decline in serum risk of hyponatremia associated with these drugs: older
sodium is slow and gradual (≥48 h), cerebral swelling age, polypharmacy, menstruation, surgery, underlying re-
and neurologic symptoms are minimized by these adap- nal disease, psychiatric condition, and female gender,
tive processes, even if the absolute reduction of serum among others (Van Amelsvoort et al., 1994; Kuz and
sodium is large. In acute hyponatremia, a rapid decrease Manssourian, 2005).
in serum sodium can overwhelm these protective mecha- The mechanisms whereby CBZ and OXC cause hy-
nisms, causing swelling of the brain and the development ponatremia are not entirely clear; however, a peripheral
of neurologic symptoms (Adrogué and Madias, 2000a; process—the induction of excessive water reabsorption in
Bhardwaj, 2006). the collecting tubule—is thought to be the cause (Ranta
In the past, it had been assumed that the likelihood of and Wooten, 2004).
brain damage from hyponatremia was directly related to Currently no consistent view exists on the association
either a rapid decline in plasma sodium or a particularly between CBZ or OXC dose and hyponatremia (Ranta and
low level of plasma sodium. Recent studies have demon- Wooten, 2004). It is likely that a degree of individual

Epilepsia, Vol. 47, No. 12, 2006


susceptibility exists for those cases in which CBZ or OXC and irreversible, even when clinical symptoms are mild
causes symptomatic hyponatremia. (Adrogué and Madias, 2000a). Hypertonic saline (3%), the
Hyponatremia secondary to CBZ and OXC is more most common treatment for acute symptomatic hypona-
common in clinical practice than is seen in the clinical tremia, causes a quick decline in brain volume, thereby
trials, but most of these patients are asymptomatic. Hy- lowering intracranial pressure. Treatment should target in-
ponatremia, if it occurs, tends to develop within the first 3 creases in serum sodium to more than 120 to 125 mEq/L.
months of drug treatment. Routine monitoring of plasma Importantly, aggressive treatment of hyponatremia with
sodium is not necessary, except for patients with diseases hypertonic saline solution can be also hazardous, because
or medications predisposing to hyponatremia (e.g., renal this approach can provoke shrinkage of the brain that trig-
diseases, diuretics) and may also be advisable in patients gers ODS and can cause neurologic dysfunction includ-
exhibiting related symptoms (blurred vision, weakness, ing quadriplegia, pseudobulbar palsy, seizures, coma, and
headache, confusion, and worsening seizures). Advanced even death (Reeves et al., 1998; Adrogué and Madias,
age is consider a risk factor, and therefore elderly patients 2000a; Riggs, 2002).
should be monitored (Smith, 2001; Dong et al., 2005). On the basis of the available data, it seems prudent to
Treatment can involve removal of the precipitating fac- correct the sodium concentration at a rate of 0.5 mEq/L/h.
tors (such as diuretics or nonsteroidal antiinflammatory However, in young women at a risk for respiratory ar-
drugs) or water restriction; dose reduction, and if required, rest, severe neurologic sequelae, and death, a rate of 1
discontinuation of the CBZ or OXC therapy (Smith, 2001; to 2 mEq/L/h has been used (Soupart and Decaux, 1996;
Ranta and Wooten, 2004), should be considered at sodium Adrogué and Madias, 2000a); higher correction rates ap-
levels of ≤120–125 mEq/L. pear to be well tolerated in children (Sarnaik et al., 1991).
Increasing evidence indicates that brain demyelinating le-
Clinical features
sions may occur in patients despite a careful correction of
The manifestations of hypotonic hyponatremia are
hyponatremia (Ayus et al., 1992; Leens et al., 2001; Bhrad-
largely related to dysfunction of the CNS and are more
waj, 2006). It is therefore important to identify additional
conspicuous when the decrease in serum sodium con-
risk factors for brain demyelination, such as hypokalemia,
centration is large or rapid (within hours) (Reeves et al.,
hypophosphatemia, seizure-induced hypoxemia, and mal-
1998; Adrogué and Madias, 2000a). In general, symptoms
nutrition with vitamin B deficiency, and to approach treat-
of hyponatremia parallel the severity of cerebral edema.
ment accordingly.
Chronic hypernatremia is less likely to induce symptoms;
approximately half of the patients with chronic hypona- HYPERNATREMIA
tremia are asymptomatic, even with serum sodium concen-
tration less than 125 mEq/L (Reeves et al., 1998). Symp- Hypernatremia is defined as a serum sodium concen-
toms rarely occur until the serum sodium is less than 120 tration in plasma >145 mEq/L. Whereas hyponatremia
mEq/L and are more usually associated with values around may cause seizures, hypernatremia is more likely to be
110 mEq/L or lower. Children are at particular high risk a result of seizure activity (e.g., generalized tonic–clonic
of developing symptomatic hyponatremia, as they have a seizures). Intracellular glycogen is metabolized to lactate
larger brain-to-skull size ratio. in muscle during seizures. As lactate is more osmotically
Complications of severe and rapidly evolving hypona- active than glycogen, intracellular osmolality of muscle
tremia include seizures, usually generalized tonic–clonic. fibers increases, and water moves into cells, causing hy-
Seizures generally occur if the plasma sodium concentra- pernatremia. The most frequent causes of hypernatremia
tion rapidly decreases to <115 mEq/L; they represent an are cited in Table 2.
ominous sign and also a medical emergency, as they are
CNS pathophysiology
associated with high mortality (Riggs, 2002). A relatively
The same brain adaptive mechanisms that respond to
small increase in the serum sodium concentration—on the
hypoosmotic changes in osmolality also act in hyperna-
order of 5%—can substantially reduce cerebral edema;
tremia. Within minutes after hypernatremia occurs, loss
seizures induced by hyponatremia can be stopped by rapid
of water from brain cells causes shrinkage of the brain
increases in the serum sodium concentration that average
and an increase in intracellular brain cell osmolality. Cells
only 3 to 7 mEq/L (Adrogué and Madias, 2000a). Improve-
immediately respond to combat this shrinkage and change
ment in neurologic function associated with hyponatremia
in osmotic pressure by moving electrolytes across the cell
may lag days behind correction of the electrolyte abnor-
membrane, leading to partial restitution of brain volume
mality, particularly in the older patient (Luckey and Parsa,
within a few hours (rapid adaptation). The normalization
of brain volume is completed within several days (slow
Treatment adaptation) as a result of the intracellular accumulation
Treatment for acute symptomatic hyponatremia must be of organic osmolytes (Reeves et al., 1998; Adrogué and
prompt because brain pathologic processes may be rapid Madias, 2000b).

Epilepsia, Vol. 47, No. 12, 2006


Although most of the change of brain osmolality in abruptly normalized; this correction therefore may lead to
chronic hyponatremia can be accounted for by the changes convulsions, coma, and death. Seizures occur in ≤40% of
in organic osmolytes, little accumulation of these osmoles patients treated for severe hypernatremia by rapid infusion
occurs with acute hypernatremia (the development of or- of hypotonic solutions (Reeves et al., 1998).
ganic electrolyte shifts occur significantly more slowly
than the changes in serum sodium). Therefore the degree Treatment
of CNS disturbance in hypernatremia is related mainly to The goal in treating hypernatremia is to replenish body
the rate at which the serum sodium increases. In acute water, thereby restoring osmotic homeostasis and cell vol-
(within hours) hypernatremic states, water is lost from ume at a rate that avoids significant complications. The
the brain, and the acute shrinkage in brain volume (espe- speed of correction depends on the speed of development
cially in infants) results in hypernatremic encephalopathy. of hypernatremia and accompanying symptoms (Adrogué
In chronic hypernatremic states, CNS cells accumulate and Madias, 2000b; Kang et al., 2002). The rate of correc-
organic osmolytes, and brain shrinkage is minimized, as tion of chronic hypernatremia should not exceed 0.5–0.7
are CNS symptoms. In theory, rapid correction of the hy- mEq/L/h; this rate should prevent cerebral edema and con-
pernatremic state may result in cerebral edema, as water vulsions. The targeted decrease in the serum sodium con-
uptake by brain cells outpaces the dissipation of accu- centration in patients with hypernatremia, except in those
mulated electrolytes and organic osmolytes. Thus overly in whom the disorder has developed over a period of hours,
aggressive therapy carries the risk of serious neurologic is of 10 mEq/L/day. Acute hypernatremia may be treated
impairment due to cerebral edema (Reeves et al., 1998; more rapidly; in such patients, reducing the serum sodium
Adrogué and Madias, 2000b; Riggs, 2002). concentration by 1 mEq/L/h is appropriate (Reeves et al.,
However, the major factor responsible for hyperna- 1998; Kong et al., 2002).
tremic encephalopathy and the impairment of neuronal Patients with hypernatremia may be treated with hypo-
function in this state is not well understood. Hyperna- tonic fluids (hypotonic saline or dextrose solutions). The
tremic encephalopathy and death can occur in the ab- preferred route for administering fluids is orally (or via
sence of pathologic changes in the CNS (other than brain a feeding tube); if this approach is not feasible, fluids
shrinkage and increase in brain NaCl content). Investiga- should be given intravenously. Because the risk of cere-
tors have hypothesized that the combination of hyperos- bral edema increases with the volume of the infusate, the
molality and cellular shrinkage leads to alteration of the volume should be restricted to that required to correct hy-
synaptic structure and function of brain cells, leading to pertonicity (Adrogué and Madias, 2000b). Normal saline
an encephalopathic state (Reeves et al., 1998; Victor and (0.9% sodium chloride) is appropriate only in case of frank
Ropper, 2001). circulatory compromise, as it provides an effective mean
of volume expansion.
Clinical presentation
Just as in hyponatremia, the symptoms of hyperna- HYPOCALCEMIA
tremia are primarily neurologic and are related mainly Hypocalcemia is defined as a plasma calcium level of
to the rate at which the serum sodium increases (Reeves <8.5 mg/dl or an ionized calcium concentration <4.0
et al., 1998; Adrogué and Madias, 2000b). Chronic hy- mg/dl. The causes of hypocalcemia are summarized in
pernatremia is less likely to induce neurologic symptoms Table 2.
than is acute hypernatremia. Slowly increasing sodium
values, to levels as high as 170 mEq/L, are often well tol- Clinical presentation
erated. Severe symptoms usually require an acute (within The symptoms of hypocalcemia are influenced by the
hours) elevation in the plasma sodium concentration to degree of hypocalcemia and the rapidity of the decrease
>158–160 mEq/L. Values >180 mEq/L are associated in the serum ionized calcium concentration (Bringhurst
with a high mortality rate, particularly in adults (Adrogué et al., 1998). Acute hypocalcemia primary causes in-
and Madias, 2000b). Brain shrinkage induced by hyperna- creased neuromuscular excitability and tetany. In the
tremia can cause rupture of cerebral veins, with focal in- CNS, the usual manifestations of acute hypocalcemia
tracerebral and subarachnoid hemorrhages, which in turn are seizures and altered mental status (Victor and Rop-
can provoke seizures. In hypernatremic infants, convul- per, 2001; Riggs, 2002). Generalized tonic–clonic, focal
sions are typically absent, except in cases of inadvertent motor, and (less frequently) atypical absence or akinetic
sodium loading or aggressive rehydration (Adrogué and seizures can occur in hypocalcemia and may be the sole
Madias, 2000b). presenting symptom (Riggs, 2002; Mrowka et al., 2004).
Although rapid sodium loading can cause seizures, con- Nonconvulsive status epilepticus secondary to hypocal-
vulsions are more frequently seen during rapid correction cemia has also been reported (Kline et al., 1998).
of hypernatremia. In patients with prolonged hyperna- Seizures may occur without muscular tetany in patients
tremia, cerebral edema may appear when the osmolality is with hypocalcemia. Seizures occur in 20–25% of patients

Epilepsia, Vol. 47, No. 12, 2006


with acute hypocalcemia as a medical emergency, and Treatment

in 30–70% of patients with symptomatic hypoparathy- The indication for urgent therapy for hypercalcemia
roidism (Messing and Simon, 1986; Gupta, 1989). usually reflects the presence of clinical manifestations and
the underlying cause of the problem, rather than the level
Treatment of serum calcium. Severe hypercalcemia should be treated
The urgency of treatment depends on the severity aggressively. Treatment often entails hydration and ad-
of symptoms and the degree of hypocalcemia. Acute ministration of hypocalcemic agents such as intravenous
hypocalcemia is an emergency that requires prompt atten- bisphosphonate (e.g., pamidronate or zoledronate) or cal-
tion, and patients with symptomatic hypocalcemia should citonin (Bringhurst et al., 1998; Stewart, 2005) [These are
be treated immediately because of the highly associated medications used to decrease calcium serum level. Their
morbidity and mortality. Treatment with intravenous cal- mechanisms of action are numerous (e.g., inhibition of
cium is the most appropriate therapy. Doses of 100 to 300 normal and abnormal bone resorption)].
mg of elemental calcium should be infused (i.v.) over a
period of 10 to 20 min. Calcium-infusion drips should be Acute or symptomatic hypercalcemia
started at 0.5 mg/kg/h and continued for several hours, Rapid and controlled correction: first, vigorous rehy-
with close monitoring of calcium levels (Bringhurst et al., dration with normal saline should be initiated, at a rate
1998). Treatment for hypocalcemic seizures is calcium of 200 to 500 ml/h, monitoring fluid overload. Then 20–
replacement; AEDs are typically not needed. AEDs may 40 mg furosemide is given intravenously, after rehydra-
abolish both overt and latent tetany, whereas hypocalcemic tion has been achieved. Consider intravenous bisphospho-
seizures may remain refractory (Messig and Simon, 1986; nates: pamidronate (60–90 mg i.v. over a 2-h period) or
Kossoff et al., 2002; Bellazzani and Howes, 2005). Obvi- zoledronate (4 mg i.v. over a 15-min period). Second line:
ously, the treatment of hypocalcemia should be directed glucocorticoids, calcitonin, mithramycin, gallium nitrate.
at the underlying disorder, and oral calcium repletion is Chronic or asymptomatic hypercalcemia
commonly prescribed for outpatient treatment. Treatment of the underlying disorder with hypocal-
cemic diet. Consider oral bisphosphonates.
Hypercalcemia is much more common than hypocal-
cemia. However, in contrast to hypocalcemia, seizures are Hypomagnesemia is defined as a plasma concentra-
rarely associated with hypercalcemia (serum calcium level tion <1.6 mEq/L (<1.9 mg/dl). Magnesium is recom-
of ≥10.5 mg/dl). The etiologies of hypercalcemia are sum- mended for anticonvulsant treatment in preeclampsia and
marized in Table 2. eclampsia (Kaplan, 2004). The inhibition of N-methyl-D-
aspartate (NMDA) glutamate receptors and the increased
Clinical presentation production of vasodilator prostaglandins in the brain could
The most common symptoms of severe hypercalcemia explain the anticonvulsant action of magnesium (Kaplan,
are those referable to disturbances of nervous system and 2004b). Additionally, magnesium serves to stabilize neu-
gastrointestinal function (Bringhurst et al., 1998; Riggs, ronal membranes. The main causes of hypomagnesemia
2002). Symptoms of hypercalcemia depend on the under- are cited in Table 2.
lying cause of the condition, the rapidity with which it Clinical presentation
develops, and the overall physical health of the patient. Symptoms do not appear unless Mg2+ decreases to
A rapid increase to moderate (12–13.9 mg/dl) hypercal- <1.2 mg/dl, and they may not correlate well with serum
cemia frequently results in marked neurologic dysfunc- ionized Mg2+ levels. The primary clinical findings are
tion, whereas chronic severe hypercalcemia (≥14 mg/dl) neuromuscular irritability, CNS hyperexcitability, and car-
may cause only minimal neurologic symptoms (Marx, diac arrhythmias. Seizures, usually generalized tonic–
2000). clonic, can occur in neonates and adults in association
Alterations of mental status—lethargy, confusion, and with severe hypomagnesemia, at levels <1 mEq/L (Riggs,
rarely coma—are the main neurologic manifestations of 2002).
hypercalcemia. Hypercalcemia is associated with reduced
neuronal membrane excitability, and thus rarely causes Treatment
seizures. However, hypercalcemia-induced hypertensive Patients with mild, asymptomatic hypomagnesemia can
encephalopathy and vasoconstriction have been hypoth- be treated with oral magnesium (e.g., magnesium glu-
esized to give rise to seizures (Chen et al., 2004; Smith, conate), usually given in divided doses totaling 500 mg/d.
2005). Reversible cerebral vasoconstriction in a patient In the setting of seizures or symptomatic or severe (<1.2
with hypercalcemia-induced seizures has been showed by mg/dl, <1 mEq/L) hypomagnesemia, it is advisable to
cerebral angiography (Chen et al., 2004). inject 1 to 2 g of MgS over a 5-min period, to be followed

Epilepsia, Vol. 47, No. 12, 2006


by an infusion of 1 to 2 g of MgS per hour for the next Dong X, Leppik IE, White J, Rarick J. (2005) Hyponatremia
few hours. If seizures persist, the bolus may be repeated from oxcarbazepine and carbamazepine. Neurology 65:1976–
(Riggs, 2002; Dubé and Granry, 2003). Potassium and Dubé L, Granry JC. (2003) The therapeutic use of magnesium in anesthe-
magnesium levels should be monitored during therapy. siology, intensive care and emergency medicine: a review. Canadian
These dosages should be reduced in patients with renal Journal of Anesthiology 50:732–746.
Farrar HC, Chande VT, Fitzpatrick DF, Shema SJ. (1995) Hypona-
insufficiency. tremia as the cause of seizures in infants: a retrospective analysis
of incidence, severity and clinical predictors. Annals of Emergency
Medicine 26:42–48.
OTHER ELECTROLYTE ABNORMALITIES Fraser CL, Arieff AI. (1997) Epidemiology, pathophysiology, and man-
agement of hyponatremic encephalopathy. American Journal of
Potassium Medicine 102:67–77.
Unlike other electrolyte alterations, hypokalemia or Gennari FJ. (1998). Hypokalemia. New England Journal of Medicine
hyperkalemia rarely causes symptoms in the CNS, and Grikiniené J, Volbekas V, Stakisaitis D. (2004) Gender differences of
seizures do not occur. Changes in the extracellular potas- sodium metabolism and hyponatremia as an adverse drug effect.
sium level (serum levels) have predominant and profound Medicina 40:935–942.
Gullans SR, Verbalis JG. (1993) Control of brain volume during hyper-
effects on the function of the cardiovascular and neu- osmolar and hypoosmolar conditions. Annual Review of Medicine
romuscular systems. Thus severe potassium abnormality 44:289–301.
may provoke fatal arrhythmias or muscle paralysis before Gupta MM. (1989) Medical emergencies associated with disorders of
calcium homeostasis. Journal of Associated Physicians of India
CNS symptoms appear (Gennari, 1998; Riggs, 2002) 37:629–631.
In summary, seizures often represent an important clini- Hirtz D, Aswal S, Berg A, Bettis D, Camfield C, Camfield P, Crumrine
cal manifestation of electrolyte disturbances. Seizures are P, Elterman R, Schneider S, Shinnar S. (2000) Practice parameter:
evaluating a first nonfebrile seizure in children: report of the Quality
more common in patients with sodium disorders, hypocal- Standards Subcommittee of the American Academy of Neurology,
cemia, and hypomagnesemia. Successful management of The Child Neurology Society, and The American Epilepsy Society.
patient seizures begins with the establishment of an accu- Neurology 55:616–623.
Juvarra G, Bettoni L, Olivieri MF, Bortone E, Cavatorta A. (1985) Hy-
rate diagnosis of the underlying electrolyte disturbances. percalcemic encephalopathy in the course of hyperthyroidism. Eu-
For that reason, complete serum chemistry, including mea- ropean Neurology 24:121–127.
surements of electrolytes, especially sodium, calcium, and Kang SK, Kim W, Oh MS. (2002) Pathogenesis and treatment of hyper-
natremia. Nephron 92:14–17.
magnesium, should be part of the initial diagnostic workup Kaplan PW. (1998) Reversible hypercalcemia cerebral vasoconstriction
in adult patients with seizures. Early identification and with seizures and blindness: a paradigm for eclampsia? Clinical Elec-
correction of these disturbances are necessary to control troencephalography 29:120–123.
Kaplan PW. (2004a) The EEG in metabolic encephalopathy and coma.
seizures and prevent permanent brain damage, as AEDs Journal of Clinical Neurophysiology 21:307–318.
alone are generally ineffective. All physicians should be Kaplan PW. (2004b) Neurologic aspects of eclampsia. Neurology Clinics
aware of these clinical conditions and have an understand- 22:841–861.
Kline CA, Esekogwu VI, Henderson SO, Newuton KI. (1998) Non-
ing of the underlying medical disorders, for this may pro- convulsive status epilepticus in a patient with hypocalcemia. Journal
vide the means of controlling the disease and initiate a of Emergency Medicine 16:715–718.
rapid and appropriate therapy. Kossoff EH, Silvia MT, Marel A, Carakushansky M, Vining EPG. (2002)
Neonatal hypocalcemic seizures: case report and literature review.
Journal of Child Neurology 7:236–239.
Kunze K. (2002) Metabolic encephalopathies. Journal of Neurology
REFERENCES 249:1150–1159.
Kuz GM, Manssourian A. (2005) Carbamazepine-induced hypona-
Adrogué HJ, Madias NE. (2000a) Hyponatremia. New England Journal tremia: assessment of risk factors. Annals of Pharmacotherapy
of Medicine 342:1493–1499. 39:1943–1946.
Adrogué HJ, Madias NE. (2000b) Hypernatremia. New England Journal LaRoche SM, Helmers SL. (2003) Epilepsy in the elderly. Neurologist
of Medicine 342:1581–1589. 9:241–249.
Ayus JC, Wheeler JM, Arieff AI. (1992) Postoperative hyponatremic Leens C, Mukendi R, Foret F, Hacourt A, Devuyst O, Colin MI.
encephalopathy in menstruant women. Annals of Internal Medicine (2001) Central and extrapontine myelinolysis in a patient in spite
117:891–897. of careful correction of hyponatremia. Clinical Nephrology 55:248–
Bellazzani MA, Howes DS. (2005) Pediatric hypocalcemic seizures: a 253.
case of rickets. Journal of Emergency Medicine 2:161–164. Lin CC. (2005) EEG manifestations in metabolic encephalophathy. Acta
Bhardwaj A. (2006) Neurological impact of vasopressin dysregulation Neurologica Taiwan 14:151–161.
and hyponatremia. Annals of Neurology 59:229–236. Luckey AE, Parsa CJ. (2003) Fluids and electrolytes in the aged. Archives
Bringhurst FR, Demay MB, Kronenberg HM. (1998) Hormones and dis- of Surgery 138:1055–1060.
orders of mineral metabolism. In Wilson JD, Foster DW, Kronenberg Marx SJ. (2000) Hyperparathyroid and hypoparathyroid disorders. New
HM, Larsen PR (Eds) Williams textbook of endocrinology, 9th ed. England Journal of Medicine 343:1863–1875.
WB Saunders, Philadelphia, pp. 1155–1178. Messing RO, Simon RP. (1986). Seizures as manifestation of systemic
Browne TR, Holmes GL. (2001) Primary care: epilepsy. New England disease. Neurology Clinics 4:563–584.
Journal of Medicine 344:1145–1151. Mrowka M, Knabe S, Klinge H, Oden P, Rosenow F. (2004) Hypocal-
Chen TH, Huang CC, Chang YY, Chen YF, Chen WH, Lai SL. (2004) cemic generalized seizures as manifestation of iatrogenic hy-
Vasoconstriction as etiology of hypercalcemia-induced seizures. poparathyroidism months to years after thyroid surgery. Epileptic
Epilepsia 45:551–554. Disorders 6:85–87.
DeLorenzo RJ, Towne AR, Pellock JM, Ko D. (1992) Status epilepticus Oguni H. (2004) Diagnosis and treatment of epilepsy. Epilepsia 45:13–
in children, adults, and elderly. Epilepsia 33:15–25. 16.

Epilepsia, Vol. 47, No. 12, 2006


Ranta A, Wooten GF. (2004) Hyponatremia due to an additive effect of flux, and changes in brain excitability. Epilepsy Research 32:275–
carbamazepine and thiazide diuretics. Epilepsia 45:879. 285.
Reddy VR, Moorthy SS. (2001) Electroencephalographic and clinical Smith PEM. (2001) Clinical recommendation for oxcarbazepine. Seizure
correlation of hyponatremia induced during transurethral resection 10:87–91.
of the prostate. Annals of Neurology 50:554–555. Smith SJ. (2005) EEG in neurological conditions other than epilepsy:
Reeves WB, Bichet DG, Andreoli TE. (1998) Posterior pituitary and wa- when does it help, what does it add? Journal of Neurology, Neuro-
ter metabolism. In Wilson JD, Foster DW, Kronenberg HM, Larsen surgery and Psychiatry 76:8–12.
PR (Eds) William’s textbook of endocrinology, 9th ed. WB Saunders, Soupart A, Decaux G. (1996) Therapeutic recommendations for man-
Philadelphia, pp. 341–372. agement of severe hyponatremia: current concepts on pathogenesis
Riggs JE. (2002) Neurological manifestations of electrolyte distur- and prevention of neurologic complications. Clinical Nephrology
bances. Neurology Clinics 20:227–239. 46:149–169.
Rose BD, Post TW. (2001) Clinical physiology of acid-base and elec- Stewart AF. (2005). Hypercalcemia associated with cancer. New Eng-
trolyte disorders.,5th ed. McGraw-Hill, New York. land Journal of Medicine 352:373–379.
Sarnaik AP, Meert K, Hackbarth R, Fleishmann L. (1991) Manage- Van Amelsvoort T, Bakshi R, Devaux CB, Schabe S. (1994) Hypona-
ment of hyponatremic seizures in children with hypertonic saline: tremia associated with carbamazepine and oxcarbazepine therapy: a
a safe and effective strategy. Critical Care Medicine 19:758– review. Epilepsia 35:181–188.
762. Victor M, Ropper AH. (2001) Adams and Victor’s principles of neurol-
Scwartzkroin PA, Baraban SC, Hochman DW. (1998) Osmolarity, ion ogy, 7th ed. McGraw-Hill, New York.

Epilepsia, Vol. 47, No. 12, 2006