Water Intoxication, Hyponatremia, and Brain Edema

Neurologic abnormalities associated with water intoxication may arise in acute oliguric/anuric renal failure, as well as in many other settings. The kidney’s capacity to excrete from water as dilute urine is the chief mechanism for prevention of water intoxication. In acute renal failure this homeostatic mechanism is lost, and neurologic dysfunction develops hours to days after the onset of renal failure, depending on initial water balance and the rate of additional free water intake. Individuals with sodium values as low as 120–125 mEq/L often remain asymptomatic. Symptoms become more prevalent once the serum sodium has fallen below 120 mEq/L.

Signs and symptoms of water intoxication may include headache, nystagmus, nausea, vomiting, diaphoresis, weakness, generalized tremulousness, ankle clonus, and the development of muscular irritability with coarse fibrillary twitching. Mental status changes range from apathy to progressive anxious restlessness, through agitation, confusion, or forgetfulness, to obtundation [Bhananker et al., 2004; Riggs, 2002]. It is possible that underlying predilections to migraine, anxiety, or other neurologic conditions may influence the symptomatic expression of water intoxication. The rate of deterioration in neurologic function ranges from gradual to rapid; the course ranges from linear to stepwise, and the severity ranges from mild to severe.

Children are at particularly high risk for the development of sudden decompensation due to brain edema at higher serum sodium concentrations than adults because they usually have higher brain:skull ratios. The immature brain often reaches adult size by 6 years of age, whereas adult skull size may not be achieved until 16 years of age [Moritz and Ayus, 2002]. Because of this vulnerability, the outcome of children whose water intoxication is overlooked may be worse than that for adults with similar duration and degree of excessive free water retention. Systemic aspects of water intoxication include cardiovascular compromise or pulmonary edema. These complications further jeopardize brain function owing to impaired oxygenation, provision of glucose, and removal of toxic metabolites of brain metabolism. Hyponatremia may result in seizures, increasing cerebral energy demand and the rate at which toxic byproducts of metabolism accumulate. Brain edema may develop and increase intracranial pressure, further impairing cerebral circulation. The edema is due to osmotically mediated flow across the blood–brain barrier (BBB), diluting extracellular electrolytes and then intracellular electrolytes.

If hyponatremia associated with neurologic decompensation remains uncorrected, convulsions, coma, and death due to brain herniation or complications of generalized convulsions may follow in quick succession. Under experimental conditions, the increase in brain water required to produce neurologic symptoms is about 3 percent, with an associated decrease in concentration of intracellular cations estimated to be 20 percent [Dodge et al., 1960].

Cerebral edema per se is unlikely to be the cause of many of the early neurologic signs and symptoms of water intoxication because these symptoms can be produced under experimental conditions without cerebral edema, and because cerebral edema in isolation does not necessarily produce a similar constellation of signs and symptoms. Exquisitely focal enhancement of neuronal excitability accompanies elevation (within certain bounds) of extracellular potassium ([K⁺]_o ) and reduction of extracellular hydrogen ion ([H⁺]_o). This state of ionic enhancement of highly regulated excitability is associated with similarly highly regulated changes in brain interstitial extracellular osmolarity. Reduction of osmolarity enhances neuronal excitability and synaptic transmission, while increases in osmolarity decrease excitability and synaptic transmission [Rosen and Andrew, 1990; Somjen, 1998]. Maintenance of low (isosmotic) cerebral interstitial sodium ([Na⁺]_o) concentration enhances synaptic transmission via the voltage-dependant inward calcium ion (Ca²⁺) currents of presynaptic neurons. The integrity of the system is maintained by the fact that, as certain critical elevations of [K⁺]_o are achieved, counter-regulatory partial inactivation of presynaptic currents produces a fall in [Na⁺]_o and interstitial calcium ([Ca²⁺]_o). Regulatory events occur that inhibit excessive excitation and prevent energy failure, excessive accumulation of toxic byproducts, and maldistribution of ions [Somjen, 2002]. This is a subject of considerable complexity, the discussion of which exceeds the confines of this chapter. Among other complexities is the probability that the characteristics of these ionic gradients may vary in various brain regions, a subject about which a considerable amount remains to be discovered. Much of what is currently understood is limited to the hippocampus. However, the general principles of the maintenance of brain to plasma ratios are likely to be fairly uniform across brain regions. The importance of these gradients to the proper function of the central nervous system (CNS) is represented by the considerable energy that is expended in order to maintain the actions of adenosine triphosphatase pumps, selective ion channels, and aquapores at the BBB to maintain different ionic concentrations in the brain interstitial fluids and cerebrospinal fluid (CSF) from those found in plasma [Schielke and Betz, 1992; Somjen, 2002]. This extraordinary energy demand is exemplified by the high density of mitochondrial brain capillary endothelia, required to maintain active transport to and from the cerebral interstitial compartment [Oldendorf et al., 1977]. In addition to other expenditures, a considerable amount of energy is devoted to the maintenance of a lower resting cerebral interstitial potassium concentration ([K⁺]_o) than elsewhere in the body; the ion/solute brain barrier also maintains lower resting-state [HCO₃⁻]_o and calcium [Ca²⁺]_o, but higher [Na⁺]_o, magnesium [Mg²⁺]_o, chloride [Cl⁻]_o, and, as already noted, [H⁺]_o than is found in plasma [Somjen, 2002].

The mechanisms and effects of disturbances in ionic gradients and solute concentrations within particular compartments can readily be seen to differ on the basis of the nature of perturbation. While shifts of ions and water in relationship to the osmolarity of adjacent compartments are normal within the context of cerebral autoregulation, deleterious examples are to be found in many disease states. Thus, given the extraordinary amount of energy expenditure required to maintain steady state and the minute compensations that occur in particular regions of brain, it can be seen that hypoxic-ischemic injury, with exhaustion of energy reserves and accumulation of a variety of ions, metabolic byproducts, and excitotoxic intermediates, produces one pattern of dysfunction. On the other hand, primarily osmotic provocations to maldistribution of ions and solute across the various compartments can be seen to produce a very different pattern of disturbance (the pattern seen in cerebral water intoxication or other sources of cerebral edema), so long as sources of energy continue to be supplied to brain. Excessive changes in plasma osmolarity may generate anisosmotic forces that overwhelm the compensations imposed by the BBB and disturb cerebral interstitial osmolarity and osmolality. BBB permeability for water is greater than that for ions. Water intoxication represents an acute form of hyposmolar plasma, which produces one pattern of cerebral compartmental ionic shifts that, at some point (when the capacity for renal compensation is exceeded), is the result of the entry of excessive water into the interstitial spaces of brain. The appearance on magnetic resonance imaging (MRI) in this situation shows cortical sulcal narrowing, T2 hyperintensity, restricted diffusion, and diffuse pial enhancement, changes characteristic for water intoxication [Yalcin-Cakmakli et al., 2010].

It has been demonstrated recently that the amount of glial plasma membrane expression of the water transport protein, aquaporin-4 (AQP4), correlates with the degree of vulnerability for water intoxication-associated brain swelling [Yang et al., 2008]. Interestingly, underexpression of astroglial AQP4 provides protection from brain swelling associated, under experimental conditions, not only with water intoxication, but also with focal cerebral ischemia and bacterial meningitis. On the other hand, underexpression renders experimental animals more vulnerable to brain injury from the vasogenic edema associated with brain tumor, brain abscess, hydrocephalus, or cortical freeze-injury. AQP4 plays additional roles, including exerting an influence on the rate of astrocyte migration during brain development, and in the fostering of glial scar formation, as well as enhancing sound- or light-evoked potentials and in modifying threshold and duration of experimentally induced seizures [Verkman et al., 2006]. The role that AQP4 may play, beyond that of water transport in neurological dysfunction associated with water intoxication, remains to be defined. It has been demonstrated that there is regional variation in AQP4 expression and function, with the perivascular, rather than endothelial, AQP4 being responsible for development of cerebral water intoxication [Amiry-Moquaddam et al., 2004]. There is experimental evidence that seizures may enhance cerebral water intoxication, and that this effect may be greater in female than male rats.

A different pattern of brain ion and solute disturbance is produced if the brain is acutely exposed to circulating substances that increase plasma osmolality. Glucose, ketoacids, ketone bodies, and monocarboxylic acids are among the most important of such substances because they may be transported across the blood brain barrier to achieve an intracellular cerebral location with which they exert osmotic influence that increases intracellular water volume, hence cellular size. This increased brain cellular volume, within the closed cranial compartment, may then reduce the space available to the cerebral vascular compartment, resulting in arterial ischemic stress that produces cerebral energy failure (reduced provision of substrate) as well as reduced venous clearance of the toxic intracellular byproducts of the inefficient state of cerebral metabolism. Sodium concentration gradients are of particular importance to compartmental variations in solute concentration and the associated osmolarity.

Cerebral dysfunction in the various types of ion/solute perturbations may involve depression of function (e.g., spreading cortical depression may be an example of this sort); or, in other situations, it may be associated with enhanced abnormal cerebral activities, such as seizures. These functional variations depend on the relative differences across various membranes, in the combination of sodium concentration and osmolarity within those locations, differences that alter, in concentration-dependent ways, voltage-dependent presynaptic calcium and potassium currents, characteristically enhancing one and depressing the other. In the case of water intoxication, cerebral calcium currents are increased as a consequence of dilution of the sodium concentration ([Na⁺]_o) as the presynaptic extracellular milieu is lowered, an effect that occurs while compartmental osmolarity does not significantly change [Chebabo et al., 1995]. This effect correlates with spreading hippocampal depression. A salt-depleted extracellular cerebral interstitial state, with the development of hyposmolarity rather then isosmolarity, may result in enhanced synaptic excitability rather than cortical depression, due to lowering of extracellular chloride ([Cl^–]_o], since this produces a situation where there is failure of chloride-mediated function of glycine and gamma-aminobutyric acid (GABA)-mediated inhibitory synapses [Kaila, 1994; Huang and Somjen, 1997a, b; Somjen, 1998; Rosen and Andrew, 1990]. These pathophysiological observations indicate that the neurological findings of water intoxication or other particular forms of ion and solute disturbance manifest differences that are not merely the result of one element. Acute and chronic forms of water intoxication differ to some extent in manifestations. This is because the rate of introduction of water into cellular systems may result in nonlinear effects on osmolality and the concentrations of various solutes within various cellular compartments. Some of this variation is the result of adjustments to the function of barriers and membrane channels that are governed by hormonal influences.

Treatment of hyponatremia in the patient with acute renal failure must be suited to the particular circumstances of the individual patient. Fluid restriction in early stages may be adequate for mild hyponatremia, but can be dangerous if cerebral perfusion is compromised. Selection of therapy depends upon appreciation of the cause of hyponatremia, initial rough estimation of which can be determined upon consideration of a number of important factors, particularly the extracellular volume state and urine sodium. The extracellular volume state is often overlooked, despite the fact that it is a critical matter if cerebral salt wasting is to be distinguished from the syndrome of inappropriate antidiuretic hormone excretion (SIADH). Once an approximation of the state of intravascular volume is achieved, an estimate as to whether the patient is or is not significantly deficient in sodium may be made, thereby indicating the type of fluid resuscitation, if any, that should be provided.

The nature of the hyponatremic state having thus been parsed, the conditions that may produce hyponatremia, as well as hypernatremia (Table 102-1), may be addressed, with appropriate tests or recognition of the role that a chronic or acutely presenting condition might have exerted. Maintenance of circulation, in some instances, requires acute judicious administration of fluid, in which case isotonic sodium usually is permissible, pending further work-up. Volume expansion with hypotonic saline in a hyponatremic patient poses risks if the patient is actually sodium-depleted systemically. The decision to restrict fluids is appropriate if there is evidence for SIADH, a diagnostic theory that ought to be resisted if the patient has depleted intravascular volume. There are situations where hypertonic saline should be considered. Dialysis may be necessary in some patients [Bhananker et al., 2004; Riggs, 2002]. The rate of sodium correction is a particularly important consideration. Excessively rapid correction poses the danger of development of central pontine myelinolysis. In children, it is recommended that correction at the rate of approximately 1 mEq/L/hour be achieved, until the patient becomes alert and seizure-free, plasma sodium becomes 125–130 mEq/L, or serum sodium level is increased by 20–25 mEq/L, whichever occurs first. If seizures persist, or if there are signs of increased intracranial pressure (especially if these signs are worsening), the sodium concentration may be corrected at a rate of 4–8 mEq/L for 1 hour (if tolerated), or until seizures stop. Assuming that total body water comprises 50 percent of body mass, administration of 1 mL/kg of 3 percent NaCl solution will increase plasma sodium by approximately 1 mEq/L [Moritz and Ayus, 2002].

Table 102-1 Causes of Hyponatremia and Hypernatremia

Hyperkalemia

During the first 48 hours of anuric acute renal failure from prerenal causes there is loss of as much as 70–80 percent of renal outer medullary potassium secretory channels and 35–40 percent of the activity of potassium channel inducing factor. Cardiac and pulmonary manifestations of hyperkalemia generally precede and are greater threats for survival than neurologic ones. Cardiac dysfunction is usually the earliest and most ominous clinical sign of hyperkalemia. However, rare instances of hyperkalemia of acute renal failure presenting as a neurologic sign (e.g., striated muscle paralysis) rather than as cardiac decompensation have been described [Cumberbatch and Hampton, 1999].

Within the BBB, elevation of extracellular potassium ([K⁺]_o) depolarizes neuronal membranes in a nonlinear fashion. As the elevation of [K⁺]_o increases, countervailing increases in inward sodium currents attenuate the extent to which depolarization results, probably preventing wide fluctuations in the functional milieu of excitable cells and membranes. Significant [K⁺]_o elevation, or, for that matter, diminution, may have drastic functional consequences within the CNS. In the case of elevation of interstitial potassium ion concentrations to levels ranging from the usual 3–3.5 mM to 5–6.25 mM, enhanced excitability and synaptic transmission is the dominant effect in neural tissues, such as hippocampal slices. On the other hand, concentrations of >8 mM begin variously to cause depression of excitability and conductance, and at certain concentrations to induce spontaneous epileptiform discharges. Elevation of serum potassium concentration reflects a complex set of equilibria. Factors include the degree of displacement of potassium from the intracellular compartment, as the result of acidemia and the state of dilution or concentration of body fluids (the balance of free water intake and output). Hyperkalemia may provoke smooth or striated muscle weakness, owing to lowered membrane resting depolarization potentials, delayed depolarization, rapid repolarization, or slowed cardiac and peripheral nerve conduction velocities [Chantler, 1988]. Correction of metabolic acidosis, with infusion of calcium or glucose, insulin, and, in some instances, administration of a β₂-adrenergic receptor stimulant such as salbutamol, may shift the circulating potassium excess to safer intracellular loci [Kemper et al., 1996]. Management may involve the use of ion exchange resins or dialysis.

Particularly important causes of acute hyperkalemia involve muscular trauma, rhabdomyolysis from trauma or burns, and succinylcholine administration to susceptible individuals in the setting of acute muscle damage. Catecholamine elevation in the setting of hypothermia may produce hyperkalemia due to changes in the intracellular/extracellular distribution of potassium. A list of causes of hyperkalemia is found in Table 102-2.

Table 102-2 Causes of Hypokalemia and Hyperkalemia

Hypokalemia

Hypokalemia is often encountered in the management of critically ill patients; some of the more common causes of hypokalemia are summarized in Table 102-2. One of the more frequently encountered situations involves the partitioning of potassium between the extracellular and intracellular spaces, which is affected by glucose and insulin metabolism, the renin-angiotensin-aldosterone system, and circulating catecholamines. Hypokalemia occurs in the setting of several different forms of renal tubular acidemia. Management of potassium is a particularly important aspect of the treatment of individuals with diabetic ketoacidosis. Clinical manifestations of hypokalemia, as is true of hyperkalemia, tend to involve smooth or striated muscle. The effects of potassium on the electrocardiogram (EKG) provide a valuable and acutely available adjunct to other tests intended to disclose potassium status. Among the neuromuscular conditions of importance is hypokalemic periodic paralysis, which is reviewed in Chapter 96.

Uremic Encephalopathy

Uremia is an extremely complicated, and as yet incompletely characterized, metabolic state that results from the failure of renal mechanisms for:

It occurs when glomerular filtration rate has declined to less than 10 percent of normal. It is fatal if untreated. Most patients with acute uremia have experienced proportional injury to tubular and glomerular systems. Bicarbonate wasting occurs but is, in part, compensated for by the retention of nonchloride anions, such as sulfate and phosphate. The result is high anion gap acidosis with normal or increased serum potassium concentration. Sodium and chloride levels remain normal, unless free water excretion is impaired. Brain edema is uncommon in uremic encephalopathy because most of the osmotically active molecules that accumulate in uremia are small molecules that equilibrate readily across the BBB [Smogorzewski, 2001]. The occurrence and degree of uremic encephalopathy correlate poorly with renal function, as measured by the degree of blood urea nitrogen abnormality. It does appear that several guanidino compounds that are subject to significant elevation in uremic patients (creatinine, guanidine, guanidino-succinic acid, and methylguanidine) are capable of causing abnormal neuronal hyperexcitability that triggers seizures in experimental models of uremia, and may also precipitate cognitive disturbances [DeDeyn et al., 2001].

Disturbances of endocrine function occur in uremia, with possible elevations, especially in chronic renal failure, of parathyroid hormone (PTH), insulin, growth hormone, glucagons, thyrotropin, prolactin, luteinizing hormone, or gastrin. Elevated concentrations of PTH, associated particularly with cases of uremic decompensation of chronic renal failure, may activate second-messenger systems that alter cellular calcium hemostasis, the balance of which is viewed by many observers as a central element of the metabolic crisis that produces uremic encephalopathy [D’Hooge et al., 2003; Fraser, 1992]. PTH concentration elevations have been clearly linked to the reduction of mental status and electroencephalographic (EEG) abnormalities associated with uremic encephalopathy [Fraser, 1992; Moe and Sprague, 1994]. In chronically uremic patients, EEG abnormalities and mental and psychiatric manifestations may improve with parathyroidectomy or chemical suppression of parathyroid function [Cogan et al., 1978]. The degree of EEG abnormalities observed in the uremic state has been directly correlated with PTH levels. In one careful experimental study, it was determined that a rise in calcium concentration in gray and white matter occurred in association with nephrectomy-induced uremia, but that the degree of brain hypercalcemia was greater if thyroparathyroidectomy had been performed than if those organs had been left intact. EEG monitoring showed that EEG findings were more persistently abnormal in the thyroparathyroidectomized dogs than in those whose glands remained intact. Thus, uremic hyperparathyroidism appears to be an important negative influence on cerebral function [Akmal et al., 1984]. Exogenous toxins, infectious and inflammatory disturbances, and particularities of glomerulotubular dysfunction may also play variable roles in exacerbating uremic encephalopathy, but are not essential predisposing features for that condition.

Numerous lines of evidence suggest the considerable importance of disturbances of calcium homeostasis, membrane excitability, and neurotransmitter function as central functional abnormalities of uremic encephalopathy [Moe and Sprague, 1994]. Although extraordinarily abundant in the body, divalent cationic calcium is highly protein-bound or sequestered within organelles, including endoplasmic reticulum and mitochondria. What remains of the intracellular ionized calcium pool is at concentrations of 50–100 nM, approximately four orders of magnitude lower than [Ca²⁺] [Somjen, 2002]. The considerable transmembrane driving force that this concentration difference could exert is prevented by a high degree of membrane impermeability to calcium, and a high degree of regulation of such calcium channels as are present. The fact that such protective mechanisms are present and that free cytosolic calcium concentrations – designated [Ca²⁺]_i – are so low (much lower than that even of highly restricted free cytosolic Mg²⁺) pays tribute to the potency of the free calcium ion [Somjen, 2002]. It is important to note that there is an extraordinarily elegant functional interaction – in some instances, synergistic, and in others, antagonistic – of calcium with the other physiologically important divalent cation, magnesium. Attachment of extracellular ionic calcium ([Ca²⁺]_o) and magnesium ([Mg²⁺]_o) to negative ions on the outer surface of cell membranes has been shown to stabilize excitable membranes because a resulting increase in transmembrane voltage reduces the likelihood that voltage-gated ion channels will open [Hille, 2001]. Within the nervous system, calcium influx through voltage-gated calcium channels into presynaptic terminals is a requirement for the occurrence of synaptic transmission [Hille, 2001]. This current and the likelihood of resulting neurotransmitter release are negatively modulated by the presence of [Mg²⁺]_o [Somjen, 2002].

Acute deficiency of magnesium or calcium is the cause of cramps and tetany, due to loss of their collaborative stabilizing effect on peripheral nerve and muscle. Box 102-1 lists some of the common causes of hypocalcemia and hypo- and hypermagnesemia. The lack of associated central effects has been explained by the protective latency in concentrations of these cations within the BBB. With greater degrees of loss of this modulating effect peripherally, failure of neuromuscular transmission develops [Somjen, 2002]. On the other hand, chronic renal failure (glomerular filtration rate <30 mL/min) is one of the most common causes of acquired hypocalcemia. First, failing kidneys may inadequately perform the second hydroxylation that is essential in activating 1,25-dihydroxyvitamin D. Second, reduced glomerular function permits hyperphosphatemia to develop. Third, diminished calcitriol production impairs intestinal absorption of calcium. Fourth, deposition of calcium and of phosphorus in soft tissues occurs. The role that hypocalcemia plays in uremic encephalopathy remains uncertain. The likelihood that hypocalcemia will produce neurological manifestations is greatest in infants, as has been demonstrated for hypocalcemic seizures [Lynch and Rust, 1994]. However, there are few data specifically concerning individuals in this age group that happen to experience uremia. Among the manifestations of uremia that might be related to hypocalcemia should be those manifestations already known to occur in association with hypocalcemia without associated uremia.

Box 102-1 Causes of Hypocalcemia, Hypomagnesemia, and Hypermagnesemia

Hypocalcemia

Vitamin D deficiency

Hypoparathyroidism

Pseudohypoparathyroidism

Hyperphosphatemia

Magnesium deficiency

Acute pancreatitis

Alkalosis

Rapid correction of acidosis

Hypomagnesemia

Malabsorption

Hypoparathyroidism

Renal tubular acidosis

Diuretic therapy

Primary aldosteronism

Neonatal tetany

Hypermagnesemia

Decreased renal function

Magnesium-containing laxatives or enema preparations

Maternal magnesium sulfate treatment

Clinical symptoms that occur in uremia include seizures, encephalopathy, poor feeding, lethargy, tremulousness, abdominal distention, and gastrointestinal autonomic dysregulation. Twitching or muscular weakness (due to impeded acetylcholine release at the neuromuscular junction) or cramping (including laryngospasm), apnea, paraesthesiae, seizures, and tetany of larynx, hands, and limb also may occur. Psychiatric manifestations are important to consider in relation to uremia with hypocalcemia, since such manifestations are more common in children than adults and may include moodiness and depression. Among these various manifestations, those with particular likelihood to derive, at least in part, from uremic hypocalcemia are altered mental status, tremulousness, and the muscle cramps that occur early in the development of uremia. Hypocalcemic tetany is produced because neuronal excitability overdrives the muscular atony and may be found especially in children [Cooper and Gittoes, 2008]. The muscle fasciculations of more severe and persistent uremia could be related to hypocalcemia, as may the peculiar movement disorder termed “uremic twitching.” Uremic encephalopathy remains a complicated condition, the pathophysiology of which could be multifactorial, but hypocalcemia could play a role. At any rate, hypocalcemia deserves a place beside hyponatremia and hypomagnesemia as a mediator of uremic encephalopathy [DeDeyn et al., 1992].

The interaction between calcium and magnesium is a quite remarkable partnership when things go well, and each must be considered in situations where the other has been implicated as a cause of dysfunction. Either hypomagnesemia or hypermagnesemia may occur in the setting of chronic renal disease. The former may develop from renal magnesium wasting. Hypomagnesemia is a condition that may be quite serious. In critically ill patients, including those who manifest renal failure, development of hypomagnesemia is associated with a 2- to 3-fold increased risk of death [Rubeiz et al., 1993]. It tends to be particularly serious in infants and the elderly. The observation that hypomagnesemia may be found in as many as 47 percent of patients with hypokalemia, 27 percent of individuals with hyponatremia, and 22 percent of those with hypocalcemia [Whang et al., 1984] – disturbances common in chronic renal disease – underlines the importance of considering its role in the neurological deficits associated with uremia. The fact that, at cerebral synaptic surfaces, extracellular magnesium serves as an important inhibitor of synaptic neurotransmitter release and is an N-methyl-d-aspartate (NMDA) receptor antagonist, reducing calcium influx, also suggests the potential importance of hypomagnesemia in uremic encephalopathy. Its antagonist in that function is calcium, an agonist that enhances neurotransmitter release [Somjen, 2002]. Should hypomagnesemia play a role, the most likely contributions would be to neurological manifestations tied to hypomagnesemia in nonrenal patients, including encephalopathy and seizures [Nuytten et al., 1991; Nakamura et al., 1994]. Hypomagnesemia might play a role in the twitching and other muscular manifestations of uremia, manifestations with which it has been associated in association with hypocalcemia [Kingston et al., 1986].

Hypermagnesemia is even more interesting as a possible cause of neurological manifestations of uremia. It is a relatively uncommon condition specifically because normal renal regulation of magnesium is quite efficient, including a rapid adaptation that permits the tubular system almost entirely to eliminate reabsorption of magnesium that has entered the tubular filtrate. It is thus not surprising that hypermagnesemia is most likely to be encountered in individuals with renal failure, especially children with acute renal failure, but also in individuals of any age with end-stage renal disease (ESRD). The normal adult filtered magnesium load is more than 2 g each day. Under normal conditions, 97 percent of this load is reabsorbed and re-enters the systemic extracellular space. Two-thirds of this reabsorption takes place in the thick ascending loop of Henle, and the remainder in the proximal tubule, except for a small amount (approximately 5 percent) recovered in the distal nephron [Quamme, 1989]. Surprisingly little is known about the mechanisms for nonrenal cellular transport of magnesium [Musso, 2009]. The fact that excess magnesium may be very efficiently eliminated by the kidney protects the public at large from the rather shocking amounts of magnesium that are imbibed in the form of antacids, laxatives, cathartics, or enemas [Woodard et al., 1990].

Many individuals with ESRD have only mild hypermagnesemia, likely because magnesium is readily dialyzable [Navarro-Gonzalez et al., 2009]. The initial presentation of hypermagnesemia is usually during the oliguric onset of renal failure. During that phase of severe renal dysfunction, magnesium supplementation may greatly worsen the degree of hypermagnesemia, particularly in instances where there is associated uremic acidemia. However, serum magnesium levels return to normal during the diuretic phase. In individuals with ESRD, magnesium-containing antacids and cathartics may worsen the hypermagnesemia. Neurological manifestations in uremic patients to which hypermagnesemia might contribute include lethargy, moodiness, depression, paraesthesiae, striated and smooth muscle weakness, and neuropathic changes in cardiac conduction, autonomic cardiovascular regulatory abnormalities, disorders of smooth and striated muscle function, and autonomic aspects of gastrointestinal function. Conditions that might worsen uremic hypermagnesemia are hypothyroidism, Addison’s disease, familial hypercalciuric hypercalcemia, and milk alkali syndrome. As with other electrolyte disturbances, clinically significant hypomagnesemia is found more commonly in infants and elderly individuals, usually in association with renal failure.

It appears likely that some combination of effects produced by the presence of low-molecular-weight, fast-acting toxic solutes that are not excreted in renal failure may contribute to the neurological and other abnormalities of chronic renal failure. Among the dozens of unexcreted solutes that might produce such effects are urea, creatinine, hippuric acid, polyamines, polypeptides, guanidino compounds, acetoin, myoinositols, sulfates, aliphatic and aromatic amines, phenols, purines, indoles, glucuronates, spermine, dl-homocysteine, orotate, and glycine [Arieff et al., 1976; D’Hooge et al., 2003]. These compounds have different capacities for the penetration of nervous tissues and also may have effects on blood vessels, membranes, enzymes, neurotransmitters, or receptors. Many of these potentially toxic chemicals, so quietly and efficiently removed by the normal kidney, are less efficiently removed from circulation by dialysis.

It has long been known that cerebral rates of utilization of glucose, oxygen, and high-energy phosphate compounds fall in uremic encephalopathy, apparently because of reduced demand rather than energy failure. To some extent this may be a protective adaptation [Mahoney et al., 1984], although it is possible that the reduction is due in part to failure of synaptic transmission. In uremic dogs, brain high-energy phosphates and glucose were normal, indicating normal energy reserve, as was the brain energy charge, representing the proportion of the adenine nucleotide made up by high-energy phosphates. In this study, the redox state was also high; hence the oxygen supply to brain cells was not limited. It was concluded that, in uremia, changes in energy metabolism were related, not to energy supply, but rather to energy demand [Mahoney et al., 1984]. A positron emission tomography (PET) study of uremic humans also suggested decreased brain energy demand, although a dysregulated metabolic state could not be excluded [Kanai et al., 2001]. Interestingly, the degree of reduction of oxygen metabolism was greatest in frontal cortex, the brain region that has shown the greatest degree of atrophy in individuals that have been on long-term hemodialysis [Savazzi et al., 1995]. These were studies of adults rather than children. Separate risk factors for cortical atrophy with greater emphasis in frontal cortex in adults are chronic hypertension and arteriosclerosis [Linder et al., 1974], the former being a factor that could affect outcome of children and adolescents with uremic renal failure.

It is not as yet known whether these indications of global brain metabolic reduction mask regional or focal excesses of utilization (in conjunction, for example, with focal seizure activity or “twitch-myoclonus”), or whether some aspects of this reduction may injure rather than protect the brain. Observed reduction in activity of the pentose phosphate shunt, an important source of reducing equivalents for maintenance of myelin and other synthetic tasks, may represent compensatory reduction of a temporarily dispensable energy expenditure. On the other hand, reduced flux in this pathway interferes with the maintenance of myelin. Interestingly, the uremic reduction in overall cerebral metabolic rate is not accompanied by reduction in cerebral blood flow, suggesting an unusual and as yet unexplained form of energy supply–demand uncoupling. Disturbances of the efficiency with which energy metabolism is carried out, as well as a number of the other forms of dysfunction already considered in the central nervous system, could produce changes in the pH of the CNS and its various compartments which could affect neurologic function [Arieff et al., 1976].

Uremic synaptosomal preparations confirm diminished activity of the metabolic pumps associated with Na⁺/K⁺ and Ca²⁺ adenosine triphosphatases and disturbances, not only in calcium, but also in cellular magnesium and potassium homeostasis. Evidence suggests that creatinine and acidic derivatives of guanidine metabolism (e.g., methyl guanidine and guanidinosuccinic acid) inhibit physiologic responses to GABA and glycine, disturb synaptic transmission in the CA1 region of the hippocampus, and elevate the excitatory tone of certain neuronal populations. Guanidino compounds, phenol, and spermine, among the first uremic small molecules to have been proven to exert definable deleterious effects on brain, alter various membrane ionic conductances by means of voltage- or ligand-gated channels. These include the NMDA receptor complex, which variously enhances inward calcium or outward potassium currents [D’Hooge et al., 2003].

Sufficient concentrations of some of these various small-molecule compounds are capable of engendering clonic seizures under experimental conditions, and it is possible that they are responsible for such classic manifestations of uremic encephalopathy as uremic “twitch-myoclonus.” Uremic myoclonus has also been associated with elevation of CSF phosphate to concentrations in excess of 3.8 mg/mL, perhaps reflecting a particular sensitivity of the brainstem reticular formation to this chemical [Chadwick and French, 1979]. Hypercalcemia is a known cause of myoclonic encephalopathy with seizures and dysarthria. Hypophosphatemia may also contribute to development of seizures in some patients [Rivera-Vazquez et al., 1980]. Toxicity of guanidinosuccinic acid is more marked in the posthypoxic state [Torremans et al., 2004], owing to the generation of superoxides and hydroxyl free radicals that have been found to produce glial cell death under experimental conditions [Hiramatsu, 2003]. It is of interest that many of the small molecules associated with uremia may play important positive roles in normal brain, perhaps as free-radical scavengers. Factors that may account for toxicity of these same molecules during renal failure likely include loss of closely regulated and carefully compartmentalized concentrations and enhanced transformation of nontoxic and metabolically useful ones into toxic molecules.

An important example of this process is free-radical-stimulated transformation of arginosuccinic acid into guanidinosuccinic acid [Cohen, 2003]. The generation of that toxic intermediate is enhanced in proportion to urea concentration [Aoyagi, 2003]. The complex state of uremia includes other pertinent and, as yet, incompletely understood or characterized metabolic and neurotransmitter disturbances, including the possible rise of glycine concentration in critical locations and fall in GABA concentrations in others. Uremic disturbance of tryptophan metabolism results in accumulation of kynurenine neurotransmitters that may provoke seizures, alter consciousness, or produce neuronal injury or cell death [Topczewska-Bruns et al., 2002]. Older data concerning uremic depression of metabolism of nucleotides, catecholamines, and amino acids involved in neurotransmitter synthesis [Fraser et al., 1985] may remain pertinent. Uremia may disturb the transport of amino and organic acids that activate excitatory or inhibitory synapses [Biasioli et al., 1986; Deferrari et al., 1981]. Although recent data on this subject are not abundant, one useful summary of available evidence suggests that low plasma levels of tryptophan and elevations of sulfuro-amino acids and of branched chain amino acids, among other abnormalities, might play a role [Furst, 1989].

Pathologic studies of uremic encephalopathy suggest variable degrees of generalized neuronal degeneration. In some instances, perivascular necrosis and demyelinative changes are discerned. Abnormalities may be emphasized in cerebral cortex, subcortical and brainstem nuclei, or cerebellum. In persons dying of acute uremic encephalopathy, Alzheimer type II astrocytes may be found [Norenberg, 1994]. Subdural hemorrhages are found in less than 3 percent of cases of chronic renal failure with uremia [Fraser and Arieff, 1997].

Although uremic encephalopathy occurs in patients without a preceding history of serious renal disease, the majority of the 16,000–20,000 cases that occur in the United States annually are found in patients who are on chronic dialysis for ESRD – a category that includes some 200,000 individuals. Care should be taken before diagnosis, as depression or frustration with chronic disease is accepted as adequate explanation of behavioral changes in individuals with ESRD. In patients with new-onset renal failure associated with uremia, an even wider differential diagnosis must be entertained as possible causes for neurologic deterioration. Difficulty may arise in instances in which new-onset renal disease with uremia pursues an indolent but subacutely progressive course. In each of these various groups, it must also be remembered that neurologic signs may precede definite clinical or biochemical evidence of renal failure.

Acute uremic encephalopathy produces deterioration of higher cortical function at a rate that varies from slowly progressive to fulminant. These changes persist and perhaps worsen in a chronic uremic state requiring hemodialysis. The earliest characteristic changes, often subtle or insidious, include inattention, indecisiveness, irritability, and diminished intellectual agility. These changes may be improperly ascribed to depression. They are often more apparent to caregivers than to the patient. They may be overlooked in children or may be falsely ascribed to uncooperativeness or irritability. Standardized assessment of vigilance with digit span or serial subtraction may be useful in following patients at risk. A peculiar dyspraxic hesitancy of speech is a common and distinctive clue, usually dyspraxia without dysnomia or other associated aphasia [Martinez et al., 1978].

Lethargy, somnolence, anorexia, nausea, vomiting, pruritus [Zucker et al., 2003], and disturbance of the sleep–wake cycle are other common early manifestations. Episodic confusion, disinterest in surroundings, poor ability to concentrate, or impairment of recent memory may develop, interspersed with more lucid intervals. Occasionally, especially in persons with fulminant renal failure, acute agitation, delirium, psychosis, coma, or catatonia suggests the presence of uremic encephalopathy [Souheaver et al., 1982]. Higher cortical function deficits may worsen as a consequence of duration of hemodialysis therapy [Kimmel et al., 1993]. In such instances, the effects of an intoxicating drug (e.g., corticosteroids, propranolol, cimetidine, levetiracetam, phenobarbital, or tricyclic antidepressants) must be excluded. Uremic encephalopathy may produce signs suggestive of Wernicke–Korsakoff syndrome [Jagadha et al., 1987].

The development of tremor is a particularly reliable early sign of uremic encephalopathy and should prompt careful mental status evaluation. Both action (e.g., ataxic) and postural tremors of irregular amplitude may occur. Asterixis in persons with renal failure is another important sign of uremic encephalopathy but is seen in other metabolic encephalopathies that impair attentiveness. The asterixic flap is not an active movement but appears to occur because patients fail to maintain voluntary motor extension of the wrists or feet. The rapidity of the flap does not, however, resemble the slower relaxation of effort seen with inattention. Central inhibition of sustained motor neuron activity has also been proposed in explanation, and the phenomenon has been called a variety of “negative myoclonus.” Similar impersistence is observed with sustained eye closure or forced smiling. Truncal asterixis also occurs and may be so severe that it mimics epileptic drop attacks [Young and Shahani, 1986]. These various manifestations may improve with dialysis. Data on this subject remain scarce. A report of three adults with abnormal movements in association with uremia requiring dialysis noted either generalized or gait dyskinesias. In all three of the individuals, basal ganglia imaging changes were found (hyperintensities or hypointensities in the region of the lenticular nuclei). The lesions and the dyskinesias gradually resolved with adjustment of treatment of the uremia [Wang et al., 1998].

With progressive obtundation, encephalopathy becomes less intermittent and a wider variety of neurologic dysfunction is displayed. Along with more severe disturbances of orientation, memory, cognition, and judgment, primitive reflexes (e.g., snout, root, grasp) may emerge. Transient loss of hearing or vision (uremic amaurosis) may occur. Either may persist for several days. Visual loss may result from either optic nerve or cortical dysfunction, possibly owing to edema. Localization is readily ascertained by the absence or presence of the pupillary light reflex. Abducens palsy only occasionally complicates uremia. It is far more common in hypertensive encephalopathy. Seizures, usually generalized tonic-clonic, occur in 20–40 percent of children with uremic encephalopathy, typically at the time of onset of renal failure. They are especially common in individuals in whom renal failure is fulminant, as is seen in acute glomerulonephritis and other causes. Seizures are seldom the only sign of uremia. Their occurrence may, however, presage an ensuing rapid decline in renal function with multiple manifestations. In acute renal failure, they are more commonly brief generalized motor than focal motor seizures. Epilepsia partialis continua may develop in some cases. Seizures occurring in the later stages of acute uremia generally signify the development of other complications, such as infection or electrolytic disturbances, during the diuretic phase of resolving acute renal failure or as consequences of overzealous dialysis.

Muscle twitching or fasciculation, especially in the distal extremities, is common in acute renal failure. Some patients report that such activity is preceded by distal extremity muscle ache or cramping. Multifocal uremic stimulus-sensitive myoclonus, which Adams termed twitch-convulsive, often emerges as uremic stupor develops [Tyler, 1976]. Restless leg phenomenon is not uncommon in uremic encephalopathy. Tetany (i.e., tonic muscle irritability, carpopedal spasm, Trousseau sign) may develop in uremia and may not respond to calcium supplementation. Choreoathetosis and even hemiballism may be observed. Moderate to severe motor weakness (including alternating hemiplegia) may follow. In patients with chronic renal failure/ESRD, acute weakness must be distinguished from pre-existing changes related to neuropathy or hyperparathyroidism (see later). Hyperkalemia must be excluded. Rarely, signs of autonomic failure are noted, some of which may be manifestations of uremic neuropathy [Yildiz et al., 1998]. Cardiovascular autonomic dysregulation in uremia is a cause of considerable morbidity and elevates risk of mortality. It is important to measure the presence and extent of such dysfunction at the bedside. Dysfunction may include loss of parasympathetic, sympathetic, and cardiac baroreceptor responses. Unanticipated deficits may imperil patients during dialysis because of hypotension [Robinson and Carr, 2002]. In uremic diabetic individuals requiring chronic dialysis, autonomic dysfunction may result in inadequate atrial stretching that impairs secretion of atrial natriuretic factor [Zoccoli et al., 1992].

Uremic encephalopathy may develop at any time during the presentation and management of individuals with renal failure, whether acute or chronic. Given the complexity of the biochemical changes associated with uremic encephalopathy, great care must be taken to detect and manage readily correctable metabolic perturbations, such as disturbances of sodium, potassium, phosphate, and magnesium. Individuals with the combination of diabetes and uremia may have hypoglycemia, hyperglycemia, or diabetic ketoacidemia. In some instances, depending to some extent on the causes of uremia, abnormalities of amino acid concentration may be identified. Chronic anemia may, in some instances, require correction before normal mentation is restored. Serum osmolality and pH must be ascertained. Seizures, subdural or other intracranial hemorrhage, intracranial thromboembolic disease, cerebral edema, hypertensive encephalopathy, or serious infection should be excluded.

Among other treatable conditions that may require consideration are endocrinopathy or vitamin deficiency states; it should also be recognized that, in some instances, neurologic improvement may lag behind adequate correction of readily measurable metabolic parameters. Some abnormalities (e.g., emotional and intellectual) may respond quickly to dialysis, whereas others (e.g., motor and sensory) respond more slowly, persisting for an uncomfortable interval. This latency may be related to the inefficiency of dialysis in clearing unmeasured toxic intermediates. Among such substances are guanido or phenol adducts, myoinositols, and phenolic and indolic acids [Deguchi et al., 2002]. Drug screening, EEG, evoked potentials, brain imaging, bacterial cultures, and lumbar puncture may be indicated in individuals with uremic encephalopathy to detect alternative or related diagnoses. Any question of increased intracranial pressure suggested by focal neurologic signs and symptoms must be investigated urgently. Subdural or intracranial hemorrhages, stroke, and brain edema are among the causes to be excluded [Brouns and DeDeyn, 2004]. It is especially important to exclude hypertensive encephalopathy, although the contribution of this entity may be difficult to untangle from various metabolic disturbances.

The presence of disturbances of mentation (especially if acute) or of lateralized findings (sometimes suggestive of intracranial hemorrhage) or meningismus are particularly ominous. Cranial nerve signs should also provoke urgent assessment at any stage of renal failure management, particularly if they occur in a pattern that suggests progressive brainstem failure. In some instances, these signs are asymmetric and changeable, especially in instances where a remediable metabolic cause is found. Onset of coma associated with progressive brainstem failure represents a medical emergency. If coma deepens without treatment of uremia, progressive brainstem failure leading to death – more frequent in the past than currently – may follow. It may be more difficult in patients with chronic renal failure to distinguish uremic encephalopathy from encephalopathy due to water intoxication or hypertension. It is frequently difficult to ascertain exactly what metabolic stresses have provoked uremic encephalopathic decompensation in patients with chronic renal disease. In some instances, several therapeutic interventions may need to be undertaken.

In acute uremia, the EEG usually demonstrates generalized irregular but bisynchronous low-voltage slowing, particularly in patients whose blood urea nitrogen level is in excess of 60 mg/dL. The severity of these changes and prevalence of associated paroxysms roughly correlate with the further degrees of blood urea nitrogen elevation and degree of clinical encephalopathy. Slow alpha-dominant rhythm, with occasional theta bursts and characteristic prolonged bursts of bisynchronous slow-sharp activity or spike and wave, may be found. Bilateral spike discharges may accompany myoclonic jerks, and generalized electroconvulsive discharges in association with generalized convulsive seizures may also occur, possibly more commonly in patients with hypomagnesemia. Photomyoclonus and photic driving may be present. Rarely, the EEG may be normal, despite uremic encephalopathy [Röhl et al., 2007]. Bursts of high-voltage 12- to 13-Hz vertex sharp activity may be seen in drowsiness, spindles may be absent in stage 2 sleep, and high-voltage slow bursts may occur with wakening. EEG abnormalities may persist for quite some time, especially in patients with chronic renal failure for whom many months of dialysis may be required before restoration of a normal EEG pattern is seen. Deteriorations in blood urea control or other indications of transient worsening of renal function may be associated with transient intrusion of diffuse delta and theta waves, generalized spike-wave discharges, or heightened sensitivity to photic stimulation.

Infrequently, brain imaging in acute uremic encephalopathy may disclose subdural hemorrhage. Treatment may resolve encephalopathy, improve function, or in some instances fail. Some patients manifest a gyriform increase in T2-weighted signal or similar abnormalities on MRI of parietal and occipital subcortical areas, changes that reverse with treatment and must be distinguished from changes suggesting hypertensive encephalopathy. Generally, brain imaging is not of much practical value in straightforward uremic encephalopathy as it is often normal [Schmidt et al., 2001]. Abnormalities, when present, may be transient and of uncertain significance. In individuals with preceding chronic renal failure who develop uremic encephalopathy, MRI may show changes due to atrophy or visually indistinguishable corticosteroid pseudoatrophy.

Elevated lumbar CSF pressure may be found in individuals with uremic encephalopathy and usually resolves with dialysis. The decision to perform a lumbar puncture must be carefully weighed when severe encephalopathy is present, given the risk for herniation. It is far from clear that lumbar puncture increases the risk for herniation, but the performance of such a procedure represents a risk that is avoidable. Even without urgent performance of that test, appropriate broad-spectrum antibiotic therapy for possible infectious causes of deterioration can be undertaken. Cultures of blood and dialysate should be obtained when indicated and lumbar puncture can be performed if still needed, once it is clear that the risk of herniation has declined. CSF protein concentration may be elevated, and pleocytosis may be found. In such cases, an underlying infectious cause, such as human immunodeficiency virus, can be sought. However, these changes may occur without identification of any treatable process and may be related to uremic alteration of BBB function.

The primary treatment of uremic encephalopathy is dialysis, with scrupulous attention to water balance, electrolytes, blood pressure, and ventilation. Consideration must be given to parathyroidectomy or chemical parathyroid suppression. Response to dialysis may be rapid or require many days. Fixed deficits may develop, especially when uremic encephalopathy is complicated by hypertension or CNS hemorrhage. Excessive or too rapid dialysis must be avoided because rapid shifts in water or solutes in various compartments may lead to alternative forms of neurologic decompensation. Only limited data are available concerning the possible neurophysiological or pathophysiological bases for progressive brain dysfunction due to chronic uremia. An early attempt to categorize such changes as might be found on postmortem analysis identified no distinctive pathology [Olsen, 1961]. That functional changes do occur in children with chronic renal disease has been documented [Rotundo et al., 1982; Fennell et al., 1990a, b; Crocker et al., 2002; Bawden et al., 2004]. The severity of deficits correlates with age of onset of renal failure, and includes difficulties with fine motor coordination, social adjustment, verbal and nonverbal learning and memory, and other measures of intelligence. Improvement in outcome in the wake of renal transplant is suggested by some but not other outcome studies [Fennell et al., 1984, 1990a, b].

Seizures should suggest re-evaluation for hypertension, electrolyte or water imbalance, infection, or intoxication (commonly, penicillin or a phenothiazine). Persistent seizures should be treated with antiepileptic drugs. Phenytoin, phenobarbital, and carbamazepine have been the most frequently employed antiseizure medicines in this setting, in part because of the considerable familiarity with the safe and effective use of such drugs in renal failure and dialysis. Phenytoin should be used cautiously. Uremia may increase hepatic clearance of phenytoin while, at the same time, hypoalbuminemia may increase free phenytoin concentration, owing to diminished protein binding. These effects often balance one another, but not invariably. It is wise to assess free phenytoin concentrations frequently in patients with uremic encephalopathy and seizures.

Hypertensive Encephalopathy

The designation ‘hypertensive encephalopathy’ is generally reserved for hypertensive patients with alteration of consciousness and diffuse or multifocal CNS dysfunction, in whom there is no better or more complex etiologic explanation. Malignant hypertension, as a cause of the neurologic abnormalities of hypertensive encephalopathy, can arise in association with a number of underlying illnesses. The causes of malignant hypertension in children vary according to age [Flanigan and Vitberg, 2006]. Malignant hypertension is rare in neonates, although it may arise as the consequence of renal failure or congenital adrenal hyperplasia [Spoudeas et al., 1993]. In this age group, approximately two-thirds of cases are related to renovascular thrombosis (spontaneous or associated with asphyxia, cyanotic heart disease, disseminated intravascular coagulopathy, or umbilical artery catheterization). Nearly 20 percent of cases are due to CNS disturbances, and approximately 8 percent are caused by tumors (e.g., Wilms’ tumor, neuroblastoma) or coarctation. When hypertensive encephalopathy occurs in the first year of life, it carries a high risk of morbidity and mortality, owing to the severity of the illnesses that typically underlie pressure elevation at this young age. Causes include aortic coarctation and polycystic kidneys (each accounting for about one-third of such cases in young patients), nephritis (16 percent), and hemolytic-uremic syndrome (7 percent). The remaining cases are due to tumors that generate Cushing’s syndrome (e.g., neuroblastoma, corticotropin-secreting ganglioneuroblastoma), high doses of adrenocorticotropic hormone used to treat infantile spasms, and various forms of renovascular disease. No cases of so-called central (primarily CNS-mediated) hypertension were described in the Boston Children’s Hospital series of cases of malignant infantile hypertension [Ingelfinger, 1982]. No cases designated as representing central hypertension are to be found in the slightly earlier study by Uhari and colleagues in Sweden, either [Uhari et al., 1979]. Both studies point out that severe arterial hypertension of childhood is often unrecognized until the child presents with neurological findings.

In children older than 1 year of age, roughly two-thirds of cases are caused by inflammatory or infectious parenchymal renal disease. These include hemolytic-uremic syndrome, acute glomerulonephritis, and collagen vascular diseases (particularly systemic lupus erythematosus). Renal or aortic vascular abnormalities, such as renal artery stenosis, kidney malformations (multicystic or dysplastic kidneys), and tumors (Wilms’ tumor, neuroblastoma, pheochromocytoma), account for the remaining one-third in most centers. However, renal graft rejection may be the most frequently encountered cause of hypertensive encephalopathy in centers that perform many kidney transplants. Immunosuppression employed in such cases may increase the risk for acute hypertension, even without graft rejection [Primavera et al., 2001; Proulx et al., 1993; Still and Cottom, 1967; Stocker et al., 2003; Zangeneh et al., 2003]. More than 40 percent of patients with malignant hypertension develop significant neurologic complications, including encephalopathy. One or another of these neurologic complications was lethal in 20 percent of patients, particularly cerebral thrombosis or hemorrhage [Flynn and Tullus, 2009]. However, increasing sophistication in imaging has, particularly with the advent of MRI, applied the term reversible posterior leukoencephalopathy to at least some of these cases [Pavlakis et al., 1997]. Although the fatality rate has undoubtedly declined, fatalities still occur, especially as the result of intracranial hemorrhage [Schwartz et al., 1995b].

The risk for hypertensive encephalopathy is related to the rapidity and severity of blood pressure increases from any given baseline [Flynn and Tullus, 2009]. Risk is higher in acute renal failure caused by acute glomerulonephritis or hemolytic-uremic syndrome than it is in essential hypertension or chronic renal failure. Acute glomerulonephritis or hemolytic-uremic syndrome should be suspected in any child older than 1 month of age with unexplained hypertensive encephalopathy, even when initial laboratory findings are minimal. Some inflammatory illnesses that cause acute hypertensive renal failure in children, such as hemolytic-uremic syndrome, may have direct effects on the CNS beyond those provoked by severe hypertension. There is increasing appreciation of the manner in which the renin-angiotensin system acts in the development of hypertensive crises. This has included experience that suggests that treatment with nicardipine represents an advance over the use of sodium nitroprusside [Patel and Mitsnefes, 2005].

Generalized severe headache is almost universal with severe hypertension. Seizures and visual loss are other common early manifestations of hypertensive encephalopathy [Wright and Mathews, 1996]. Headache develops hours to days after the initiating blood pressure crisis and may be accompanied by lethargy, projectile vomiting, meningismus, or edema of the eyelids and ankles. Ophthalmoscopic findings of hypertensive encephalopathy were initially defined and classified according to the venerable scheme of Keith, Wagener, and Barker [1939]. Problems with this approach are seen in adults, as well as in children. Papilledema (KWB group 4) is present in only one-third of children with other clinical findings of hypertensive encephalopathy. The modified Scheie classification [Scheie, 1953] may be more useful, bearing in mind that children may have retinal changes consistent with grades 2 (obvious arterial narrowing with focal irregularities due to retinal arterial spasm), 3 (as with grade 2, but with the addition of retinal hemorrhages and white exudates), or 4 (as with grade 3 but with papilledema in addition). Retinal arteriolar spasm is a far more characteristic and important sign of the onset of hypertensive encephalopathy than the additional changes seen in grades 3 or 4 [Flynn and Tullus, 2009]. The white exudate (cotton-wool spots) due to ischemic infarction represents an important funduscopic finding of hypertensive encephalopathy; non-ophthalmologists involved in the care of children at risk for hypertensive encephalopathy should diligently seek to identify this finding in appropriate clinical settings [Browning et al., 2001].

The earliest non-ophthalmologic signs in newborns and infants with hypertensive encephalopathy include irritability, lethargy, and hypotonia. Infants without hypertensive encephalopathy may exhibit opisthotonos, fever, and unresponsiveness. The level of consciousness in older children consists of fluctuating confusion, irritability, and restlessness that may progress to coma. Encephalopathy in older children typically develops after 12–36 hours of headache and is often heralded by seizures, more commonly generalized than focal [Dedeoglu et al., 1996]. In virtually all cases of hypertensive encephalopathy with seizures, systolic and diastolic blood pressures are more than four standard deviations above the mean for age. Status epilepticus may further elevate systolic and diastolic blood pressures in more than 10 percent of cases. Elevation of blood pressure by four standard deviations above the mean for age should, in no case, be ascribed to seizures alone [Proulx et al., 1993]. Seizures without persistently associated mental status changes occasionally occur as the sole initial clinical manifestation of hypertensive encephalopathy.

Muscle twitching and myoclonus may occur. Focal neurologic signs may be present in various combinations of aphasia, scotomas (retinal, optic nerve, or cortical), cranial neuropathy (especially abducens or facial nerves), and focal motor weakness (especially hemiparesis). In severe cases, rapidly progressive brainstem failure may precede death, unless effective treatment is initiated [Lindfors-Lonnkvist and Jakobsson, 1994; Zangeneh et al., 2003]. Hypertension-associated occipital blindness, with additional features such as headache, lethargy, transient motor deficits, confusion, visual hallucination, and convulsive seizures (generalized more commonly than focal), constitutes a syndrome that has been termed reversible posterior leukoencephalopathy [Hinchey et al., 1996; Kwong et al., 1987; Saatci and Topaloglu, 1994; Sebire et al., 1995]. This clinically distinctive subcategory of hypertensive encephalopathy was first described in individuals receiving immunosuppression with cyclosporine. It occurs most commonly, however, in children or adults who develop acute hypertension in the setting of either acute or chronic nephrotic conditions.

Posterior Reversible Encephalopathy Syndrome

Posterior reversible encephalopathy syndrome (PRES, also termed reversible posterior leukoencephalopathy syndrome or RPLS) is thought to represent a disorder of cerebral autoregulation occurring in the setting of acute hypertension [Pande et al., 2006]. Nephrotoxic (e.g., acyclovir) or cytotoxic (e.g., cyclosporine) drugs and treatment with high doses of methylprednisolone enhance risk for the development of this syndrome, especially in patients receiving excessive fluid loads [Ikeda et al., 2001]. Cytotoxic drugs may enhance risk for PRES because they compromise the BBB [Mukherjee and McKinstry, 2001; Neuwelt, 2004]. The respiratory distress of fluid-overloaded patients may increase risk because of elevation of venous “back-pressure” of the cerebral venous circulation. Attention has been drawn to the development of MRI changes consistent with PRES in the hemisphere contralateral to predominantly hemiconvulsive seizures, suggesting that seizures themselves may have a role in the genesis and evolution of PRES [Obeid et al., 2004]. Interestingly, there has been recent demonstration that imaging changes of PRES are an important element of the MRI appearance of encephalopathy in the setting of thrombotic thrombocytopenic purpura, and that the severity of those changes tends to correspond with the severity of renal dysfunction [Burrus et al., 2010].

Brain imaging in PRES usually illustrates fairly symmetric and extensive abnormalities within 24 hours of clinical onset that are much more apparent on MRI than on computed tomography (CT). With MRI, T2-weighted bright and T1-weighted dark abnormalities usually are due to edema rather than infarction and tend to be located in the posterior parietal/occipital cortical ribbon, especially in the subjacent white matter. Changes are both cortical and subcortical, and are distributed similarly to the changes that are seen in watershed infarction. The cerebellum may be involved. Similar changes may be found elsewhere, such as in the basal ganglia or brainstem, but such changes are less common. Occasionally extensive hyperintense signal is seen in the brainstem and occasionally there is generalized white-matter edema. The changes are hypointense on T1WI weighting and hyperintense on T2WI weighting. Gradient-echo techniques may demonstrate characteristic petechial hemorrhages [Kandt et al., 1995; Weingarten et al., 1994]. In some instances, clinical and radiographic changes of reversible posterior leukoencephalopathy or of hypertensive encephalopathy do not resolve for days to as many as 8 weeks after control of hypertension. Reduction of dosage of medications such as cytotoxic or immunosuppressive agents may be required in persistent cases [Dedeoglu et al., 1996; Hinchey et al., 1996; Primavera et al., 2001].

Clinical findings and radiographic changes of PRES are similar to those found in the syndrome of cyclosporine neurotoxicity. The typical clinical appearance of PRES includes fairly sudden onset of severe headache, confusion, and visual disturbance. In a series of 22 episodes of PRES in children with renal disease, the mean age of the children was 12 years. Interestingly, for a West Virginia cadre, 45 percent of the children were African American. The prevalence of PRES in the West Virginia ESRD program for children was 9 percent. It is important to note that blood pressure was normal at the onset of PRES in 18 percent of the children. Half had considerable blood pressure elevation. Seizures occurred at the onset in 82 percent of cases, chiefly generalized convulsive seizures, with status epilepticus in only one case. Mental status was altered in 32 percent, while visual changes (black spots in the visual fields, visual hallucinations, or cortical blindness) occurred in 36 percent. Several children had recurrent PRES episodes [Onder et al., 2007]. Recurrent PRES is not uncommon [Girigsen et al., 2010]. Symptoms promptly resolve after correction of blood pressure with medications or dialysis. PRES has been described as a complication of parturition, potentially affecting the health of both mother and child [Long et al., 2007].

In cyclosporine-associated imaging changes resembling PRES, edema may be exacerbated by the effects of cyclosporine on BBB permeability rather than by any direct toxic effect of cyclosporine on the brain [Lopez-Garcia et al., 2004; Primavera et al., 2001]. Intracranial hemorrhage is more typically associated with cyclosporine-induced than other forms of hypertensive encephalopathy, probably potentiated by cyclosporine-induced thrombocytopenia [Schwartz et al., 1995a]. Changes resembling PRES develop in a minority of patients who have had long-term dialysis followed by administration of interferon-alpha in preparation for renal transplantation. Some of these individuals have chronic hepatitis C infection [Fatih et al., 2003]. Other differential considerations are acute cerebral ischemia (ACI) or acute cerebral hyperemia (ACH). The clinical setting is helpful in distinguishing these entities. PRES occurs in association with hypertension, although in some children, the clinical and imaging syndrome has arisen with normal or minimally elevated blood pressure. ACI occurs in the setting of a hypotensive event, and ACH in association with the occurrence of seizures, rapid decompression of chronic subdural hemorrhage, or rapid restoration of circulation due to angioplasty, arterectomy, or stenting [Coutts et al., 2003].

Focal clinical features of hypertensive encephalopathy are not always transient. Aphasia, optic nerve scotomas, and hemiparesis may indicate the occurrence of brain, cranial nerve, or brainstem infarction. Unilateral infarction of some portion of the anterior optic pathways is especially characteristic. Infarction may be more common in patients who have had long-standing unrecognized hypertension. It also occurs in individuals who experience hypotensive episodes due to overly aggressive management of blood pressure elevation [Sebire et al., 1995; Browning et al., 2001]. These data suggest the importance of early specialist evaluation of visual function in at-risk individuals to assure that deteriorating vision is urgently evaluated and treated. It is as yet unclear if infarctions are due to vasculopathy or to impairment of blood flow related to edema and hypotension.

Information concerning the pathologic changes that occur in hypertensive encephalopathy is scant. Perivascular edema (with or without microhemorrhages) and swelling of astrocytes and myelin have been described [Lumsden, 1970].

The exact nature of the pathophysiology of hypertensive encephalopathy is not fully understood, but two major theories are advocated. An older view states that encephalopathy is the result of excessive cerebral vasoconstrictive autoregulation, stimulated to protect cerebral microvascularity from high pressure. This reduction of microcirculatory flow is believed to compromise capillary integrity and result in edema, vascular necrosis, microinfarction, and petechial hemorrhages. This sequence has been demonstrated in experimental models [Finnerty, 1972