Electrolytes Disturbances and Seizures

Abstract

Electrolyte disturbances are frequently encountered in daily clinical practice. The diagnosis of these abnormalities is commonly made from routine laboratory findings, and they are not usually of clinical significance. However, they may sometimes lead to serious complications when overlooked or not treated appropriately. Electrolyte abnormalities may affect many organs and tissues, including the brain. Most of the clinical manifestations of these derangements are predominantly neurologic and parallel the severity of neuronal damage. Furthermore, these disorders may appear with seizures, or with rapidly progressive neurologic symptoms and signs, and thus require emergency treatment (Rose and Post, 2001; Riggs, 2002). Acute and/or severe electrolyte imbalances frequently cause seizures, and these seizures may be the sole presenting symptom. Seizures are especially common in patients with sodium disorders, hypocalcemia, and hypomagnesemia. Successful management of patient seizures begins with the establishment of an accurate diagnosis of the underlying electrolyte disturbance, because rapid identification and correction of the disturbance is necessary to control seizures and prevent permanent brain damage (Kunze, 2002; Riggs, 2002). A 61-year-old man was initially seen in the emergency department with nausea and emesis and, after several minutes, tonic–clonic seizures developed. The patient had a previous medical history of benign prostatic hyperplasia, and several hours before admission, he came to the radiology department to undergo a routine abdominal ultrasound examination. To fill his bladder before undertaking the ultrasound test, he drank a copious amount (4–5 L) of water. On physical examination, the patient was confused and disoriented. The neurologic examination was unremarkable. His serum electrolyte levels were as follows: sodium, 112 mEq/L; potassium, 3.4 mEql/L; serum osmolality, 235 mOsm/kg; and blood glucose, 124 mg/dl. Emergency computed tomography of the brain was normal. We diagnosed hyponatremic encephalopathy due to water intoxication and treated with intravenous 3% saline solution. In 48 h, the patient's serum sodium level increased to 136 mM. He made a full clinical recovery. It is clear that better training in management of electrolyte imbalances in patients with seizures is needed to reduce common and serious neurologic morbidity associated with these medical problems. We give an overview of the clinical aspects of electrolyte disturbances associated with seizures, with special regard to the pathophysiologic mechanisms involved and treatment recommendations. Electrolyte homeostasis in the central nervous system (CNS) is essential for brain function. Regulation of ionic balance is a critical process involving a complex array of molecules for moving ions into and out of the brain and involving blood–brain barrier function as well as mechanisms in the membranes of both neurons and glia. Alterations in ion gradients across cellular membranes can have direct and indirect effects on neuronal discharge and may facilitate epileptiform activities (Scwartzkroin et al., 1998). A variety of pathological states or conditions such as dehydration or renal failure are associated with substantial modifications of plasma osmolality and electrolyte balance. These conditions may overcome homeostatic brain systems and provoke profound consequences on brain metabolism and function. Clinical manifestations of electrolyte disturbances in the CNS are variable. In general, they represent functional disturbances of the brain, and, at least in the beginning, are generally not associated with morphologic changes in brain tissue. Because neurologic symptoms of electrolyte disorders are generally functional rather than structural, the neurologic manifestations of electrolyte disturbances are typically reversible (Kunze, 2002; Riggs, 2002). However, because functional dysfunction such as seizures can lead to structural alterations, it is important to treat the underlying disturbance before the pathology becomes permanent. Disorders of sodium and osmolality produce CNS neuronal depression, with encephalopathy as the major clinical manifestation; these disorders can also provoke CNS neuronal irritability. Similarly, hypercalcemia and hypermagnesemia produce CNS neuronal depression with encephalopathy. Conversely, hypocalcemia and hypomagnesemia cause mainly CNS neuronal irritability with seizures. In contrast, disorders of potassium rarely produce symptoms in the CNS but may be associated with muscle weakness as the major clinical manifestation (Victor and Ropper, 2001; Riggs, 2002) The main features of CNS neuronal depression and encephalopathy are confusion and slight cognitive disturbances. These features may be accompanied by headache, lethargy, weakness, tremor, and so on, usually without signs of focal cerebral disease or a disorder of cranial nerves (Kunze, 2002; Riggs, 2002). Electrolyte disorders frequently cause seizures (Table 1). Seizures are common in patients with sodium disorders, hypocalcemia, and hypomagnesemia (Victor and Ropper, 2001; Riggs, 2002). In such cases, seizures are usually generalized tonic–clonic, although partial seizures or other seizure types can occur. In all these cases, rapidly evolving electrolyte abnormalities are more likely to cause seizures than are those occurring gradually. 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). The correct diagnosis of seizures secondary to electrolyte abnormalities begins with a complete serum chemistry evaluation, including measurements of electrolytes, especially sodium, calcium, and magnesium. This workup should always be part of the initial diagnostic workup in adult patients with a first-time seizures (Browne and Holmes, 2001; Oguni, 2004). Such an electrolyte screen is particularly important in certain patient populations, such as the elderly, in which metabolic disturbances (e.g., hyponatremia or hypoglycemia) are common. Between 15 and 30% of acute symptomatic seizures among seniors occur in the setting of toxic–metabolic causes (LaRoche and Helmers, 2003). Further, identification and correction of electrolyte imbalances leading to seizures are needed to reduce morbidity and mortality associated with these medical problems. Thus in a review of 375 adult cases of status epilepticus (SE), 10% had a metabolic disorder as the primary etiology of their seizure; in this subset of patients, mortality was reported to be as high as 40% (DeLorenzo et al., 1992). It is important to note that laboratory screening tests, based on the American Academy of Neurology recommendations, are not routinely performed in children and should be ordered based on individual clinical circumstances (Hirtz et al., 2000). However, a thorough history and a comprehensive neurologic and general examination remain the cornerstone of the clinical diagnosis of epilepsy. Treatment of seizures secondary to electrolyte imbalances is determined by the underlying cause of the disturbance and should be guided by the clinical setting. In most cases of electrolyte imbalance, treatment with an anticonvulsant (AED) is not necessary as long as the underlying disturbance is rectified. Long-term administration of AEDs is not necessary (Victor and Ropper, 2001; Kunze, 2002; Riggs, 2002). Indeed, AEDs alone are generally ineffective if the electrolyte disorder persists. Changes in blood electrolytes may cause diffuse brain dysfunction, metabolic encephalopathy, and consequently EEG abnormalities. The EEG has been widely used to evaluate metabolic encephalopathies since 1937, when Berguer first observed slow brain activity induced by hypoglycemia (Lin, 2005). In general, the most prominent feature of the EEG record in encephalopathies (if a change occurs) is slowing of the normal background frequency. A gradual and progressive decline over the course of the disease may be noted if serial EEGs are performed. Disorganization of the record may develop gradually, and reactivity to photic or other types of external stimulation may be altered (Kaplan, 2004a). EEG evolution generally correlates well with the severity of encephalopathy. However, EEG has little specificity in differentiating etiologies in most encephalopathies. Particularly in metabolic encephalopathies, common EEG observations include a varied degree of slowing, assorted mixtures of epileptiform discharges, high incidence of triphasic waves (TWs), and (as a rule) reversibility after treatment of underlying causes (Kaplan, 2004a; Lin, 2005). The rate of change of electrolyte balance is more important in determining the degree of EEG abnormality than is the absolute level of a given electrolyte or metabolite. For instance, EEG changes are usually more severe in uremic encephalopathy if acute deterioration of renal function exists (Smith, 2005). Hyponatremia usually produces nonspecific slowing. Very low sodium levels may initially produce posterior slowing followed by diffuse delta activity correlated clinically with papilledema. However, a variety of other patterns have been described, such as TWs, burst of high-voltage rhythmic delta activity, and central high-voltage 6-Hz to 7-Hz activity with stimulation-induced paroxysms of delta waves. Although periodic lateralized epileptiform discharges may occur, full seizure activity is very rare (Reddy and Moorthy, 2001; Kaplan, 2004a). Early EEG changes associated with hypocalcemia include evolution from alpha through theta and delta dominance. Other EEG findings (generalized spikes, sharp-waves burst of delta activity with sharp components). Generalized paroxysmal discharges and absence SE have also been reported (Kapplan, 2004a). Neonatal records may show reversible 3- to 4-Hz spike–waves discharges (Kossoff, 2002). No strict correlation links serum calcium level to seizure threshold and/or EEG changes in hypocalcemia. In hypercalcemia, EEG changes (fast activity and burst of delta and theta slowing) appear when calcium levels reach ∼13 mg/dl. As calcium level increases, increased background slowing (largely frontal), paroxysmal theta/delta bursts, and TWs may appear (Juvarra et al., 1985; Kaplan, 2004a). Diffuse and more occipital spike–slow-wave complexes may be found, suggesting a calcium-mediated vasospastic effect in the posterior cerebral circulation, also noted with very high calcium levels (Kaplan, 1998). When calcium is normalized, the EEG usually improves, but only gradually. Hyponatremia is defined as a decrease in the serum sodium concentration to a level <136 mEq/L. Hyponatremia is reported to be the cause of seizures in 70% of infants younger than 6 months who lacked findings suggesting another cause (Farrar et al., 1995). The main causes of hyponatremia are listed in Table 2. The major dangers from acute hyponatremia are brain cell swelling and herniation. Serious symptoms, principally neurologic, may become evident when hyponatremia approaches 120 mM (Riggs, 2002). Brain adaptive mechanisms to changes in osmolality help explain these adverse events. When serum sodium decreases, cerebral edema is counteracted initially by an adaptive process known as the “regulatory volume decrease,” with the displacement of water from the interstitial space to the cerebrospinal fluid and then to the systemic circulation. This process is driven by hydrostatic pressure. Subsequently, the brain prevents swelling by the extrusion from brain cells of electrolytes. Partial restoration of brain volume occurs within ∼3 h (rapid adaptation), with the extrusion from brain cells of these electrolytes: sodium, potassium, and chloride. A second cellular adaptation mechanism to osmolality changes is the egress from the brain cells of organic osmolytes (osmotically active agents), primarily amino acids, which is almost fully achieved after 48 h (slow adaptation) (Gullans and Verbalis, 1993; Bhardwaj, 2006). These organic osmolytes, known previously as “idiogenic osmoles,” play an important role in this cellular adaptation to chronic osmolality changes. If the decline in serum sodium is slow and gradual (≥48 h), cerebral swelling and neurologic symptoms are minimized by these adaptive processes, even if the absolute reduction of serum sodium is large. In acute hyponatremia, a rapid decrease in serum sodium can overwhelm these protective mechanisms, causing swelling of the brain and the development of neurologic symptoms (Adrogué and Madias, 2000a; Bhardwaj, 2006). In the past, it had been assumed that the likelihood of brain damage from hyponatremia was directly related to either a rapid decline in plasma sodium or a particularly low level of plasma sodium. Recent studies have demonstrated that other factors influence outcome, including the age and the gender of the individual (with children and menstruant women the most susceptible) (Fraser and Arieff, 1997; Bhardwaj, 2006). Thus it is estimated that women have a 25-fold increased risk compared with men of death or permanent neurologic damage as a result of the hyponatremia (Reeves et al., 1998). Hypoxia and ischemia impair the brain adaptive mechanisms to hyponatremia and worsen the cerebral edema. This point is clinically important, because it also justifies a quick and appropriate treatment of patients' seizures. Finally, this process of adaptation by the brain is also the source of the risk of osmotic demyelination. The correction of hyponatremia triggers a “de-adaptation” process, during which the electrolytes reaccumulate rapidly in the brain cell, but the reentry of organic osmolytes occurs much more slowly. Therefore in patients with chronic hyponatremia, it has been hypothesized that rapid correction of serum sodium—before a readjustment of intracellular osmolytes concentrations occurs—results in loss of water from neurons and glia; this process carries with it the danger of provoking osmotic demyelination syndrome (ODS), associated with pontine and extrapontine demyelination (Reeves et al., 1998; Adrogué and Madias, 2000a; Riggs, 2002). However, some investigators have demonstrated that ODS does not depend on the rate of correction of hyponatremia alone but also on concurrent insults [e.g., alcoholism, anoxic brain injury, or severe liver dysfunction (Ayus et al., 1992; Bhradwaj, 2006)]. Hyponatremia has been associated with several AEDs, such as carbamazepine (CBZ) and oxcarbazepine (OXC), and occasionally with valproate (VPA) and lamotrigine (LTG) (Grikiniené et al., 2004). The frequency of hyponatremia in OXC (a 10-keto analogue of CBZ)-treated patients is even higher than in those receiving CBZ (Dong et al., 2005). The prevalence ranges—from 1.8% to 40% with CBZ and 23% to 73% with OXC—depends on the patient population studied (Dong et al., 2005; Kuz and Manssourian, 2005). Several risk factors have been reported to increase the risk of hyponatremia associated with these drugs: older age, polypharmacy, menstruation, surgery, underlying renal disease, psychiatric condition, and female gender, among others (Van Amelsvoort et al., 1994; Kuz and Manssourian, 2005). The mechanisms whereby CBZ and OXC cause hyponatremia are not entirely clear; however, a peripheral process—the induction of excessive water reabsorption in the collecting tubule—is thought to be the cause (Ranta and Wooten, 2004). Currently no consistent view exists on the association between CBZ or OXC dose and hyponatremia (Ranta and Wooten, 2004). It is likely that a degree of individual susceptibility exists for those cases in which CBZ or OXC causes symptomatic hyponatremia. Hyponatremia secondary to CBZ and OXC is more common in clinical practice than is seen in the clinical trials, but most of these patients are asymptomatic. Hyponatremia, if it occurs, tends to develop within the first 3 months of drug treatment. Routine monitoring of plasma sodium is not necessary, except for patients with diseases or medications predisposing to hyponatremia (e.g., renal diseases, diuretics) and may also be advisable in patients exhibiting related symptoms (blurred vision, weakness, headache, confusion, and worsening seizures). Advanced age is consider a risk factor, and therefore elderly patients should be monitored (Smith, 2001; Dong et al., 2005). Treatment can involve removal of the precipitating factors (such as diuretics or nonsteroidal antiinflammatory drugs) or water restriction; dose reduction, and if required, discontinuation of the CBZ or OXC therapy (Smith, 2001; Ranta and Wooten, 2004), should be considered at sodium levels of ≤120–125 mEq/L. The manifestations of hypotonic hyponatremia are largely related to dysfunction of the CNS and are more conspicuous when the decrease in serum sodium concentration is large or rapid (within hours) (Reeves et al., 1998; Adrogué and Madias, 2000a). In general, symptoms of hyponatremia parallel the severity of cerebral edema. Chronic hypernatremia is less likely to induce symptoms; approximately half of the patients with chronic hyponatremia are asymptomatic, even with serum sodium concentration less than 125 mEq/L (Reeves et al., 1998). Symptoms rarely occur until the serum sodium is less than 120 mEq/L and are more usually associated with values around 110 mEq/L or lower. Children are at particular high risk of developing symptomatic hyponatremia, as they have a larger brain-to-skull size ratio. Complications of severe and rapidly evolving hyponatremia include seizures, usually generalized tonic–clonic. Seizures generally occur if the plasma sodium concentration rapidly decreases to <115 mEq/L; they represent an ominous sign and also a medical emergency, as they are associated with high mortality (Riggs, 2002). A relatively small increase in the serum sodium concentration—on the order of 5%—can substantially reduce cerebral edema; seizures induced by hyponatremia can be stopped by rapid increases in the serum sodium concentration that average only 3 to 7 mEq/L (Adrogué and Madias, 2000a). Improvement in neurologic function associated with hyponatremia may lag days behind correction of the electrolyte abnormality, particularly in the older patient (Luckey and Parsa, 2003). Treatment for acute symptomatic hyponatremia must be prompt because brain pathologic processes may be rapid and irreversible, even when clinical symptoms are mild (Adrogué and Madias, 2000a). Hypertonic saline (3%), the most common treatment for acute symptomatic hyponatremia, causes a quick decline in brain volume, thereby lowering intracranial pressure. Treatment should target increases in serum sodium to more than 120 to 125 mEq/L. Importantly, aggressive treatment of hyponatremia with hypertonic saline solution can be also hazardous, because this approach can provoke shrinkage of the brain that triggers ODS and can cause neurologic dysfunction including quadriplegia, pseudobulbar palsy, seizures, coma, and even death (Reeves et al., 1998; Adrogué and Madias, 2000a; Riggs, 2002). On the basis of the available data, it seems prudent to correct the sodium concentration at a rate of 0.5 mEq/L/h. However, in young women at a risk for respiratory arrest, severe neurologic sequelae, and death, a rate of 1 to 2 mEq/L/h has been used (Soupart and Decaux, 1996; Adrogué and Madias, 2000a); higher correction rates appear to be well tolerated in children (Sarnaik et al., 1991). Increasing evidence indicates that brain demyelinating lesions may occur in patients despite a careful correction of hyponatremia (Ayus et al., 1992; Leens et al., 2001; Bhradwaj, 2006). It is therefore important to identify additional risk factors for brain demyelination, such as hypokalemia, hypophosphatemia, seizure-induced hypoxemia, and malnutrition with vitamin B deficiency, and to approach treatment accordingly. Hypernatremia is defined as a serum sodium concentration in plasma >145 mEq/L. Whereas hyponatremia may cause seizures, hypernatremia is more likely to be a result of seizure activity (e.g., generalized tonic–clonic seizures). Intracellular glycogen is metabolized to lactate in muscle during seizures. As lactate is more osmotically active than glycogen, intracellular osmolality of muscle fibers increases, and water moves into cells, causing hypernatremia. The most frequent causes of hypernatremia are cited in Table 2. The same brain adaptive mechanisms that respond to hypoosmotic changes in osmolality also act in hypernatremia. Within minutes after hypernatremia occurs, loss of water from brain cells causes shrinkage of the brain and an increase in intracellular brain cell osmolality. Cells immediately respond to combat this shrinkage and change in osmotic pressure by moving electrolytes across the cell membrane, leading to partial restitution of brain volume within a few hours (rapid adaptation). The normalization of brain volume is completed within several days (slow adaptation) as a result of the intracellular accumulation of organic osmolytes (Reeves et al., 1998; Adrogué and Madias, 2000b). Although most of the change of brain osmolality in chronic hyponatremia can be accounted for by the changes in organic osmolytes, little accumulation of these osmoles occurs with acute hypernatremia (the development of organic electrolyte shifts occur significantly more slowly than the changes in serum sodium). Therefore the degree of CNS disturbance in hypernatremia is related mainly to the rate at which the serum sodium increases. In acute (within hours) hypernatremic states, water is lost from the brain, and the acute shrinkage in brain volume (especially in infants) results in hypernatremic encephalopathy. In chronic hypernatremic states, CNS cells accumulate organic osmolytes, and brain shrinkage is minimized, as are CNS symptoms. In theory, rapid correction of the hypernatremic state may result in cerebral edema, as water uptake by brain cells outpaces the dissipation of accumulated electrolytes and organic osmolytes. Thus overly aggressive therapy carries the risk of serious neurologic impairment due to cerebral edema (Reeves et al., 1998; Adrogué and Madias, 2000b; Riggs, 2002). However, the major factor responsible for hypernatremic encephalopathy and the impairment of neuronal function in this state is not well understood. Hypernatremic encephalopathy and death can occur in the absence of pathologic changes in the CNS (other than brain shrinkage and increase in brain NaCl content). Investigators have hypothesized that the combination of hyperosmolality and cellular shrinkage leads to alteration of the synaptic structure and function of brain cells, leading to an encephalopathic state (Reeves et al., 1998; Victor and Ropper, 2001). Just as in hyponatremia, the symptoms of hypernatremia are primarily neurologic and are related mainly to the rate at which the serum sodium increases (Reeves et al., 1998; Adrogué and Madias, 2000b). Chronic hypernatremia is less likely to induce neurologic symptoms than is acute hypernatremia. Slowly increasing sodium values, to levels as high as 170 mEq/L, are often well tolerated. Severe symptoms usually require an acute (within hours) elevation in the plasma sodium concentration to >158–160 mEq/L. Values >180 mEq/L are associated with a high mortality rate, particularly in adults (Adrogué and Madias, 2000b). Brain shrinkage induced by hypernatremia can cause rupture of cerebral veins, with focal intracerebral and subarachnoid hemorrhages, which in turn can provoke seizures. In hypernatremic infants, convulsions are typically absent, except in cases of inadvertent sodium loading or aggressive rehydration (Adrogué and Madias, 2000b). Although rapid sodium loading can cause seizures, convulsions are more frequently seen during rapid correction of hypernatremia. In patients with prolonged hypernatremia, cerebral edema may appear when the osmolality is abruptly normalized; this correction therefore may lead to convulsions, coma, and death. Seizures occur in ≤40% of patients treated for severe hypernatremia by rapid infusion of hypotonic solutions (Reeves et al., 1998). The goal in treating hypernatremia is to replenish body water, thereby restoring osmotic homeostasis and cell volume at a rate that avoids significant complications. The speed of correction depends on the speed of development of hypernatremia and accompanying symptoms (Adrogué and Madias, 2000b; Kang et al., 2002). The rate of correction of chronic hypernatremia should not exceed 0.5–0.7 mEq/L/h; this rate should prevent cerebral edema and convulsions. The targeted decrease in the serum sodium concentration in patients with hypernatremia, except in those in whom the disorder has developed over a period of hours, is of 10 mEq/L/day. Acute hypernatremia may be treated more rapidly; in such patients, reducing the serum sodium concentration by 1 mEq/L/h is appropriate (Reeves et al., 1998; Kong et al., 2002). Patients with hypernatremia may be treated with hypotonic fluids (hypotonic saline or dextrose solutions). The preferred route for administering fluids is orally (or via a feeding tube); if this approach is not feasible, fluids should be given intravenously. Because the risk of cerebral edema increases with the volume of the infusate, the volume should be restricted to that required to correct hypertonicity (Adrogué and Madias, 2000b). Normal saline (0.9% sodium chloride) is appropriate only in case of frank circulatory compromise, as it provides an effective mean of volume expansion. Hypocalcemia is defined as a plasma calcium level of <8.5 mg/dl or an ionized calcium concentration <4.0 mg/dl. The causes of hypocalcemia are summarized in Table 2. The symptoms of hypocalcemia are influenced by the degree of hypocalcemia and the rapidity of the decrease in the serum ionized calcium concentration (Bringhurst et al., 1998). Acute hypocalcemia primary causes increased neuromuscular excitability and tetany. In the CNS, the usual manifestations of acute hypocalcemia are seizures and altered mental status (Victor and Ropper, 2001; Riggs, 2002). Generalized tonic–clonic, focal motor, and (less frequently) atypical absence or akinetic seizures can occur in hypocalcemia and may be the sole presenting symptom (Riggs, 2002; Mrowka et al., 2004). Nonconvulsive status epilepticus secondary to hypocalcemia has also been reported (Kline et al., 1998). Seizures may occur without muscular tetany in patients with hypocalcemia. Seizures occur in 20–25% of patients with acute hypocalcemia as a medical emergency, and in 30–70% of patients with symptomatic hypoparathyroidism (Messing and Simon, 1986; Gupta, 1989). The urgency of treatment depends on the severity of symptoms and the degree of hypocalcemia. Acute hypocalcemia is an emergency that requires prompt attention, and patients with symptomatic hypocalcemia should be treated immediately because of the highly associated morbidity and mortality. Treatment with intravenous calcium is the most appropriate therapy. Doses of 100 to 300 mg of elemental calcium should be infused (i.v.) over a period of 10 to 20 min. Calcium-infusion drips should be started at 0.5 mg/kg/h and continued for several hours, with close monitoring of calcium levels (Bringhurst et al., 1998). Treatment for hypocalcemic seizures is calcium replacement; AEDs are typically not needed. AEDs may abolish both overt and latent tetany, whereas hypocalcemic seizures may remain refractory (Messig and Simon, 1986; Kossoff et al., 2002; Bellazzani and Howes, 2005). Obviously, the treatment of hypocalcemia should be directed at the underlying disorder, and oral calcium repletion is commonly prescribed for outpatient treatment. Hypercalcemia is much more common than hypocalcemia. However, in contrast to hypocalcemia, seizures are rarely associated with hypercalcemia (serum calcium level of ≥10.5 mg/dl). The etiologies of hypercalcemia are summarized in Table 2. The most common symptoms of severe hypercalcemia are those referable to disturbances of nervous system and gastrointestinal function (Bringhurst et al., 1998; Riggs, 2002). Symptoms of hypercalcemia depend on the underlying cause of the condition, the rapidity with which it develops, and the overall physical health of the patient. A rapid increase to moderate (12–13.9 mg/dl) hypercalcemia frequently results in marked neurologic dysfunction, whereas chronic severe hypercalcemia (≥14 mg/dl) may cause only minimal neurologic symptoms (Marx, 2000). Alterations of mental status—lethargy, confusion, and rarely coma—are the main neurologic manifestations of hypercalcemia. Hypercalcemia is associated with reduced neuronal membrane excitability, and thus rarely causes seizures. However, hypercalcemia-induced hypertensive encephalopathy and vasoconstriction have been hypothesized to give rise to seizures (Chen et al., 2004; Smith, 2005). Reversible cerebral vasoconstriction in a patient with hypercalcemia-induced seizures has been showed by cerebral angiography (Chen et al., 2004). The indication for urgent therapy for hypercalcemia usually reflects the presence of clinical manifestations and the underlying cause of the problem, rather than the level of serum calcium. Severe hypercalcemia should be treated aggressively. Treatment often entails hydration and administration of hypocalcemic agents such as intravenous bisphosphonate (e.g., pamidronate or zoledronate) or calcitonin (Bringhurst et al., 1998; Stewart, 2005) [These are medications used to decrease calcium serum level. Their mechanisms of action are numerous (e.g., inhibition of normal and abnormal bone resorption)]. Rapid and controlled correction: first, vigorous rehydration with normal saline should be initiated, at a rate of 200 to 500 ml/h, monitoring fluid overload. Then 20–40 mg furosemide is given intravenously, after rehydration has been achieved. Consider intravenous bisphosphonates: pamidronate (60–90 mg i.v. over a 2-h period) or zoledronate (4 mg i.v. over a 15-min period). Second line: glucocorticoids, calcitonin, mithramycin, gallium nitrate. Treatment of the underlying disorder with hypocalcemic diet. Consider oral bisphosphonates. Hypomagnesemia is defined as a plasma concentration <1.6 mEq/L (<1.9 mg/dl). Magnesium is recommended for anticonvulsant treatment in preeclampsia and eclampsia (Kaplan, 2004). The inhibition of N-methyl-d-aspartate (NMDA) glutamate receptors and the increased production of vasodilator prostaglandins in the brain could explain the anticonvulsant action of magnesium (Kaplan, 2004b). Additionally, magnesium serves to stabilize neuronal membranes. The main causes of hypomagnesemia are cited in Table 2. Symptoms do not appear unless Mg2+ decreases to <1.2 mg/dl, and they may not correlate well with serum ionized Mg2+ levels. The primary clinical findings are neuromuscular irritability, CNS hyperexcitability, and cardiac arrhythmias. Seizures, usually generalized tonic–clonic, can occur in neonates and adults in association with severe hypomagnesemia, at levels <1 mEq/L (Riggs, 2002). Patients with mild, asymptomatic hypomagnesemia can be treated with oral magnesium (e.g., magnesium gluconate), usually given in divided doses totaling 500 mg/d. In the setting of seizures or symptomatic or severe (<1.2 mg/dl, <1 mEq/L) hypomagnesemia, it is advisable to inject 1 to 2 g of MgS over a 5-min period, to be followed by an infusion of 1 to 2 g of MgS per hour for the next few hours. If seizures persist, the bolus may be repeated (Riggs, 2002; Dubé and Granry, 2003). Potassium and magnesium levels should be monitored during therapy. These dosages should be reduced in patients with renal insufficiency. Unlike other electrolyte alterations, hypokalemia or hyperkalemia rarely causes symptoms in the CNS, and seizures do not occur. Changes in the extracellular potassium level (serum levels) have predominant and profound effects on the function of the cardiovascular and neuromuscular systems. Thus severe potassium abnormality may provoke fatal arrhythmias or muscle paralysis before CNS symptoms appear (Gennari, 1998; Riggs, 2002) In summary, seizures often represent an important clinical manifestation of electrolyte disturbances. Seizures are more common in patients with sodium disorders, hypocalcemia, and hypomagnesemia. Successful management of patient seizures begins with the establishment of an accurate diagnosis of the underlying electrolyte disturbances. For that reason, complete serum chemistry, including measurements of electrolytes, especially sodium, calcium, and magnesium, should be part of the initial diagnostic workup in adult patients with seizures. Early identification and correction of these disturbances are necessary to control seizures and prevent permanent brain damage, as AEDs alone are generally ineffective. All physicians should be aware of these clinical conditions and have an understanding of the underlying medical disorders, for this may provide the means of controlling the disease and initiate a rapid and appropriate therapy.