Electrolyte, Sporadic Metabolic, and Endocrine Disorders
Giuseppe Gobbi
Salvatore Grosso
Gianna Bertani
Antonella Pini
Introduction
Acute and chronic metabolic, electrolyte, and endocrine disorders may cause dysfunction or impairment of the central nervous system, including epileptic seizures.
Occasional seizures resulting from metabolic and electrolyte imbalances are typical and well-recognized events in neonates. However, seizures may develop in later childhood and adulthood as the presenting symptom of an endocrine or metabolic disturbance, and these have been reported with increasing frequency, sometimes in newly recognized clinical conditions such as primary magnesium deficiency. Metabolic disorders in which seizures are one of the main symptoms also occur with liver and kidney transplantation.4
Epilepsy as an initial and prominent symptom of unrecognized gastrointestinal disease has been described in cases of gluten intolerance.11,31,88202 Finally, there have been anecdotal reports of patients affected by concomitant endocrine, metabolic, and gastrointestinal disorders in whom seizures were the presenting manifestation.
In this chapter, the main metabolic, endocrine, and gastrointestinal disorders in which seizures or epilepsy may occur are reviewed based on the literature. The following conditions are considered:
Electrolyte disorders of sodium (hyponatremia) and magnesium (hypomagnesemia).
Renal failure (uremic encephalopathy, aluminum encephalopathy, dialysis disequilibrium syndrome, dialysis encephalopathy syndrome).
Endocrine disorders, including pituitary disorders, hypothalamic hamartoma, thyroid disorders (primary hyperthyroidism, primary hypothyroidism, Hashimoto encephalopathy), parathyroid disorders (hypoparathyroidism, hyperparathyroidism), pancreatic disorders (diabetes mellitus or nonketotic hyperglycemia, diabetic and nondiabetic hypoglycemia), and reproductive disorders.
Gastrointestinal diseases (celiac disease, orthotopic liver transplantation).
Electrolyte Disorders
Electrolyte disorders can be associated with seizures especially in neonates, but also in children and adults. Seizures may be the presenting symptom of an isolated disorder or of a disorder associated with renal or endocrine disease. Seizures may be present in cases of sodium, magnesium, and calcium imbalance. Seizures associated with sodium and magnesium imbalance are described in this section on electrolyte disorders; disturbances of calcium balance are discussed in the section on endocrine disorders.
Sodium Electrolyte Disorders: Hyponatremia
General Findings
Hypotonic hyponatremia is an electrolyte disturbance characterized by low plasma osmolality (<280 mosm/kg).29 Hyponatremia may be mild (serum sodium concentration <130 mEq/L) or severe (serum sodium concentration <120 mEq/L). Mild hyponatremia commonly occurs in about 3% to 5% of hospitalized patients14 and in 1.5% of hospitalized children.37 Usually, it is asymptomatic and requires no specific therapy. Severe hyponatremia is rare (occurring in only 0.2%),37 but it must be corrected immediately because of the risk for severe neurologic sequelae.14 Hypotonic hyponatremia may be hypovolemic, euvolemic, or hypervolemic (Table 1).
The clinical consequences of hyponatremia uncommonly manifest primarily as neurological symptoms but may occur in cases of acute (symptomatic) hypotonic hyponatremia. In this condition serum sodium concentration falls rapidly (in <24 hours) to levels <120 mEq/L, without the brain having time to adapt to the electrolyte disturbance. When an osmotic gradient occurs in the brain within a few hours, equilibrium is restored by movement of water molecules into both extracellular fluid and cells. Cerebral edema consequently develops, inducing convulsions followed by tentorial herniation, respiratory arrest, and death. The rate of change is a key element in the appearance of convulsions, and is more important than the degree of hyponatremia. The same mechanism causes seizures during rapid rehydration in cases of hypernatremia.17 Some authors18 have suggested that the ability of the brain to adapt to hyponatremia is gender related and that androgens may augment such adaptation. In children, in whom hormonal concentrations are minimal or absent, no gender difference has been found.19 Of course, the pathogenesis is complicated, and there may be other contributing factors, such as concomitant hypomagnesemia,180 a combination of hypokalemia and elevated levels of antidiuretic hormone (ADH) (diuretic-induced hyponatremia), a combination of excessive water intake and impaired renal excretion of free water caused by inappropriate secretion of ADH syndrome (SIADH),19 increased tubular sensitivity to ADH (e.g., in psychotic patients taking neuroleptics),52 and a combination of extensive extrarenal loss of electrolyte-containing fluids and intravenous replacement with hypotonic fluids in the presence of ADH activity (as in postsurgical patients).
Table 1 Classification of hypotonic hyponatremia | |||||||||||||||||||||||||||||
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Epileptic seizures have been reported in cases of diuretic-induced acute hyponatremia, SIADH acute hyponatremia, and acute water intoxication.
Diuretic-induced acute hyponatremia may be caused by a thiazide or a combination of hydrochlorothiazide and amiloride.141
The syndrome of inappropriate secretion of ADH (SIADH) is a form of chronic hyponatremia sustained by constant or intermittent secretion of ADH that is inappropriate in relation to both osmotic and volume stimuli.37 SIADH is characterized by hyponatremia without extracellular dehydration and edema and by plasma hypo-osmolality without urinary hypo-osmolality. Renal, thyroid, or adrenal insufficiency is absent. Causes of SIADH may be any of the following: Central nervous system disorders (infections, trauma, tumor, sarcoid psychosis), tumors (leukemia; lymphosarcoma; and carcinoma of prostate, ureter, pancreas, or duodenum), drugs (vincristine, vinblastine, carbamazepine, oxcarbazepine, barbiturates, amitriptyline), or pulmonary diseases (infection, tumors, asthma, pneumothorax).37 In particular, acute hyponatremia and generalized tonic–clonic seizures have been observed in infants with respiratory syncytial virus bronchiolitis. Therefore, fluid therapy in these vulnerable infants should be tailored to reduce the risk of hyponatremia.93 The syndrome has also been observed in postoperative patients with water retention caused by heart, liver, or kidney failure and in cases of excess salt depletion, as occurs in adrenal insufficiency, malnutrition, or diuretic therapy. Seizures have been reported only in cases of SIADH acute hyponatremia associated with Salmonella infection,47 ingestion of 3,4-methylenedioxymethylamphetamine (MDMA, “ecstasy”), or febrile convulsions.178
Acute water intoxication is a rare condition occurring in a variety of clinical settings, all of which involve excessive and rapid intake of free water resulting in a sudden fall of serum sodium levels to <120 mEq/L. Acute oral water intoxication is increasing in frequency, especially in infants <6 months of age, in whom it follows inappropriate administration of low-solute formula or excessive administration of water to infants who are denied formula or breast-feeding.140 In some cases, water had been given because of mistaken ideas about the correct management of diarrhea in infants or because of infant irritability (perhaps caused by neglect).140 The risk for this problem may be increased among infants of parents living in poverty. Oral water intoxication is rarer in children (0.4%) and adults (1%–4%); it has been reported in cases of children being forced to drink water or swallowing swimming pool water114 and of psychogenic polydipsia.95 Acute non-oral water intoxication has been reported following tap water enemas or excessive parenteral administration of water in hospitalized patients receiving intravenous fluid.114 It is also seen in postoperative patients with extrarenal loss of electrolyte-containing fluids undergoing parenteral replacement with hypotonic fluid, which normally leads to an increased plasma ADH concentration and a decrease in urinary output.74 In postoperative patients, excessive ADH secretion may be caused by pain or emotional stress. Most of these patients have a superimposed condition that impairs excretion of free water.37 Acute hyponatremia followed by seizures may also occur after desmopressin treatment. Desmopressin is an ADH analogue used to improve hemostasis in patients with bleeding disorders and in patients suffering from nocturnal enuresis. Therefore, fluid restriction, avoidance of hypo-osmolar fluid, and close monitoring of fluid and electrolytes are recommended in patients who undergo desmopressin therapy.59,143 The risk of imipramine administration also has to be taken into account in patients who are given desmopressin.92
In chronic hyponatremia, the osmotic gradient occurs gradually, so that diffusion of sodium chloride is sufficient and the respective volumes are kept constant. As a result cerebral edema and convulsions do not occur. On the other hand, during these adaptive changes, sodium and potassium are lost from the brain, rendering it susceptible to dehydration during correction of hypersalinity if this occurs more rapidly than the brain can recover solute.195 The suddenly higher plasma osmolality may cause dehydration and injury of the brain, leading to osmotic demyelination syndrome with central pontine myelinolysis and extrapontine demyelination.195
Clinical Description
Typical neurologic manifestations of acute symptomatic hyponatremia consist of generalized tonic–clonic seizures,
hypothermia, and respiratory failure. Nausea, vomiting, muscular twitching, and, in later phases, coma may also occur.
hypothermia, and respiratory failure. Nausea, vomiting, muscular twitching, and, in later phases, coma may also occur.
In diuretic-induced acute hyponatremia, hyponatremic seizures are usually generalized tonic–clonic, with frequent progression to status epilepticus.110 In SIADH acute hyponatremia, neurologic manifestations are headache, incoordination, disturbances of consciousness, and especially generalized tonic–clonic seizures.47,178 Persistent simple partial motor seizures and multifocal seizures have been reported in a patient with SIADH, acute intermittent porphyria, hyponatremia, and hypomagnesemia; seizures were controlled by magnesium therapy.180
Infants affected by acute oral water intoxication exhibit persistent, severe generalized tonic–clonic seizures, usually with progression to status epilepticus. The seizures are intermixed with periods of reduced responsiveness, which have been considered to represent a postictal state or persistent, clinically unapparent seizures.114 Seizures may be preceded by twitching of the eyes. Brief seizures lasting <10 minutes are rare (9% in the series of Farrar et al.74). Clinical features may also include opisthotonic posturing, restlessness, weakness, nausea, vomiting, diarrhea, polyuria or olyguria, and muscle fasciculations. Seizures are rare in older children and adults. However, in 84 of 121 cases in the literature with psychogenic self-induced acute water intoxication, generalized tonic–clonic seizures were the presenting symptom.52 Partial jacksonian seizures were reported in only one case.108 In contrast to oral water intoxication, acute nonoral water intoxication is not characterized by seizures as the presenting symptom, and generalized tonic–clonic seizures lasting several minutes have been reported only anecdotally as the presenting symptom.39 Seizures are similar to those of oral acute intoxication.
A relationship has been demonstrated between lower serum sodium levels and an increased risk of developing recurrent seizures within the same febrile illness. In fact, sodium levels were significantly lower in children with recurrent “simple” febrile seizures as compared with single febrile seizures.117 Because this finding has not been confirmed by other authors, the American Academy of Pediatrics Practice Parameter does not recommend routinely obtaining electrolytes in patients with febrile convulsions.200
The outcome is usually favorable, and in series of both infants and adults, almost all patients recovered completely after prompt correction of the electrolyte imbalance; severe brain damage is usually prevented.52 Coma and death resulting from respiratory failure, brainstem herniation, and permanent brain damage occurred only in patients who underwent treatment after respiratory failure and coma had already occurred. Permanent brain damage may take the form of diabetes mellitus, central diabetes insipidus, mental retardation, or vegetative status.18,19 Mortality has been reported in 50% of adult patients, especially women,18 and 8.4% of children.19 Vulnerability to water intoxication seems to be greater in postoperative patients, especially children19 and adult women,18 in whom the incidence of death or permanent brain damage is higher. These figures appear to be an overestimate, however, because a more recent review found a much lower mortality rate and only few cases of permanent neurologic sequelae.74
Chronic hyponatremia is less symptomatic, brain edema is not severe, and neurologically these patients may experience only minor symptoms. Nonetheless, osmotic demyelination syndrome may occur during the correction phase, producing convulsions, fluctuating levels of consciousness, and behavioral disturbances that progress to pseudobulbar palsy.195 Thus, patients with chronic hyponatremia may be more likely to become permanently impaired than those with acute hyponatremia.
Diagnostic Evaluation
Because acute hyponatremia was the cause of seizures in 56% of infants <2 years of age who experienced seizures without any obvious cause,74 a diagnosis of hyponatremia should be strongly considered in infants with long-lasting seizures or status epilepticus that is poorly responsive to antiepileptic drugs in whom evidence of another cause is lacking. Similarly, generalized seizures in psychogenic patients should be suggestive of acute hyponatremia. An accurate history is useful in investigating the vast number of possible causes of acute hyponatremia but not in emergent cases, for which only laboratory evaluations are of diagnostic value. Clinically, hypothermia associated with drug-resistant seizures or status epilepticus (in contrast to the more common situation of a rising temperature in such cases) may be a predictor of hyponatremia.74
Moreover, because hyponatremic seizures are usually occasional seizures that occur only once either as an isolated attack or in the form of repeated convulsions, a correct diagnostic evaluation first must consider all the main causes of occasional seizures, such as bacterial and viral infections, intoxication, trauma, cerebrovascular diseases and accidents, burn encephalopathy, and metabolic disturbances, including electrolyte imbalance. Laboratory determinations of serum electrolytes, urea nitrogen, creatinine, glucose, and osmolality and of urinary electrolytes, urea, creatinine, and osmolality are more important and may provide sufficient data for a correct diagnosis. In general, a condition characterized by hypovolemia and low plasma osmolality (<280 mosm/kg) together with excessive levels of total body water and sodium and an abnormally high urinary sodium concentration (>20 mEq/L) is suggestive of a primary renal disorder or of drug- or hormone-induced renal dysfunction, which is associated with renal salt wasting. Low serum sodium associated with low urinary sodium concentration (<20 mEq/L) is caused by extrarenal losses, such as vomiting, diarrhea, sweat, pancreatitis, peritonitis, ascites, burns, and muscle trauma. Water intoxication is confirmed by euvolemia associated with low plasma osmolality (<280 mosm/kg), dilute urine, and low serum sodium levels despite normal or near-normal total body sodium, whereas low serum sodium levels with high urinary sodium concentration (>20 mEq/L) suggest SIADH. A full clinical and laboratory examination is needed to investigate all the possible causes of SIADH, and the diagnosis is confirmed by normal adrenal, pituitary, thyroid, and renal excretory function. Finally, excessive levels of total body water and sodium with low plasma osmolality and low urinary sodium concentration (<20 mEq/L) may suggest nephrotic syndromes, congestive heart failure, or cirrhosis.
Electroencephalographic (EEG) examinations have not been commonly performed in acute water intoxication. Nevertheless, lack of alpha activity and presence of high-voltage slow waves requiring long periods to disappear155 and diffuse and bilateral periodic lateralizing epileptiform discharges (PLEDs) occurring in relation to hemispheric ischemic disturbance have been reported.108
Treatment
Acute hyponatremia must be promptly corrected, even when the cause is unknown, because rapid correction of sodium levels is usually well tolerated before brain adaptation against osmotic swelling is complete.199 The empiric use of hypertonic saline solution (2–6 mL of 3% sodium solution per kilogram of body weight),52 producing a rapid increase of 3 to 5 mmol/L in the serum sodium concentration, corrects hyponatremia within 4 hours, may prevent death and brain damage,183 and should be strongly considered. Further correction toward a normal serum sodium concentration should be continued during the
next 20 to 48 hours. Similar successful correction of acute hyponatremia has been demonstrated in psychogenic water drinkers, either by saline infusion alone or by a combination of saline infusion and fluid restriction,52 although cases of presumed pontine myelinolysis following fast correction of self-induced water intoxication have been reported in alcoholic, malnourished psychogenic water drinkers.199 Patients who are potentially more vulnerable to osmotic demyelination are similar to patients with polydipsia-hyponatremia syndrome, which is a chronic hyponatremic condition. Even though they experience episodes of acute water intoxication, these patients may be at risk for osmotic demyelination syndrome if an aggressive therapeutic approach with hypertonic saline solution is administered.195 Therefore, a more conservative approach, with slow correction of hyponatremia, must be taken. In addition to hypertonic correction, treatment may include intubation and assisted mechanical ventilation in cases of respiratory failure.19 Finally, special care must be taken if carbamazepine or barbiturates have been administered as treatment of recurrent seizures before hyponatremia was diagnosed. These drugs may cause SIADH, which induces water retention and complicates the clinical outcome. On the other hand, phenytoin has been reported to be the therapy of choice for SIADH, reducing seizures in neonates with SIADH developing refractory hyponatremic seizures.154
next 20 to 48 hours. Similar successful correction of acute hyponatremia has been demonstrated in psychogenic water drinkers, either by saline infusion alone or by a combination of saline infusion and fluid restriction,52 although cases of presumed pontine myelinolysis following fast correction of self-induced water intoxication have been reported in alcoholic, malnourished psychogenic water drinkers.199 Patients who are potentially more vulnerable to osmotic demyelination are similar to patients with polydipsia-hyponatremia syndrome, which is a chronic hyponatremic condition. Even though they experience episodes of acute water intoxication, these patients may be at risk for osmotic demyelination syndrome if an aggressive therapeutic approach with hypertonic saline solution is administered.195 Therefore, a more conservative approach, with slow correction of hyponatremia, must be taken. In addition to hypertonic correction, treatment may include intubation and assisted mechanical ventilation in cases of respiratory failure.19 Finally, special care must be taken if carbamazepine or barbiturates have been administered as treatment of recurrent seizures before hyponatremia was diagnosed. These drugs may cause SIADH, which induces water retention and complicates the clinical outcome. On the other hand, phenytoin has been reported to be the therapy of choice for SIADH, reducing seizures in neonates with SIADH developing refractory hyponatremic seizures.154
Magnesium Electrolyte Disorders: Hypomagnesemia
General Findings
The location of magnesium in the body is chiefly intracellular, and about half of the body content is located in bone, with high concentrations also in liver, muscle, and brain. Magnesium is the second-most-abundant intracellular cation in the body and plays an important role in neuromuscular excitability. Magnesium produces a curare-like action on neuromuscular function and has a depressant effect on the central nervous system. A direct correlation between low plasma magnesium concentrations, seizure frequency, and status epilepticus has been demonstrated in generalized idiopathic epilepsies.33 However, the reason that hypomagnesemia causes seizures is unknown. It has been suggested that hypomagnesemia may remove an inhibitory influence from the N-methyl-D-aspartate (NMDA) glutamate receptors. Then, this process may trigger neuronal depolarization. Magnesium specifically inhibits sodium flux through NMDA-type glutamate receptors.64 Chronic hypomagnesemia, as an isolated abnormality, may be caused by a reduced intestinal absorption due to transport defect or a reduced tubular filtration rate. It may be asymptomatic or symptomatic, depending on the patient’s age.77 Normal serum concentration is between 1.6 and 2.1 mEq/L. In cerebrospinal fluid the normal concentration is 2.4 mEq/L because of active transport of the ion. Symptomatic magnesium deficiency is an electrolyte disturbance defined as a serum magnesium concentration of <1.4 mEq/L (usually between 0.7 and 1.4 mEq/L). A secondary hypocalcemia caused by the inhibitory effects of magnesium deficiency on the parathyroid gland12 is frequently present, and it is associated with inappropriately low parathyroid hormone levels for the degree of hypocalcemia, as has been found in both primary and secondary hypomagnesemia.26,175
Primary hypomagnesemia (congenital hypomagnesemia, familial hypomagnesemia or primary hypomagnesemia with secondary hypocalcemia, isolated intestinal magnesium malabsorption) is a rare condition in infants. Phenotypic characterization of clinically affected patients and experimental studies of appropriate animal models have contributed to a growing knowledge of renal magnesium transport mechanisms. In that context, both autosomal-dominant and recessive models of inheritance have been reported. The autosomal-dominant variant has been found to be associated with hypocalciuria and linked to the gene FXYD2 on chromosome 11q23, which codes for a subunit of the basolateral Na-K-ATPase on the distal collecting tubule.120 In the recessive variant, defects and mechanisms for hypomagnesemia are unknown.
Hypomagnesemia may also be associated with other abnormalities in the context of specific syndromes. For example, hypomagnesemia in association with hypokalemia is suggestive of Gitelman syndrome, which also manifests with metabolic alkalosis and high renin and aldosterone levels. Gitelman syndrome is caused by an inactivating mutation in the electroneutral cation-chloride–coupled cotransporter gene SLC12A3, which is located on human chromosome 16q13 and functions as a sodium/chloride thiazide-sensitive cotransporter.138
Familial hypomagnesemia with secondary hypocalcemia is an autosomal-recessive inherited disorder related to mutations in the TRPM6 gene located on chromosome 9q21, which encodes for a transient receptor potential ion channel and leads to defects in both intestinal and renal handling of magnesium.
Finally, hypomagnesemia, hypercalciuria, and nephrocalcinosis also comprise a rare autosomal-recessive disorder in which polyuria and hyperuricemia may occur. Mutations in the paracellin-1 or CLDN16 gene located on chromosome 3q, which encodes for paracellular transport pathways, have been found.64
Secondary hypomagnesemia has been reported after removal of parathyroid neoplasm and in cases of diabetic acidosis, malabsorption syndromes caused by intestinal injury, bowel resection (for carcinoma, enteritis, mesenteric thrombosis), prolonged loss of gastrointestinal fluids, hyperaldosteronism,10 excessive use of diuretics, prolonged treatment with platinum compounds,26 and closed heart surgery.184 Frequently, it is associated with concurrent metabolic disorders, such as electrolyte deficiencies, hypo-osmolality, and septicemia, which may make it difficult to recognize hypomagnesemia. In neonates, transient hypomagnesemia is known to occur in children of toxemic and diabetic mothers, intrauterine growth retardation (IUGR) infants, or infants with transient hypoparathyroidism or maternal hypomagnesemia due to celiac disease.
Clinical Description
In general, magnesium depletion is characterized by an epileptic syndrome consisting of generalized seizures or partial seizures with single or multiple foci. There is a complicated symptomatology associated with neuromuscular irritability resulting in action-intention tremor, myoclonic jerks, startle response, generalized tendon hyperreflexia, Chvostek’s sign without concomitant Trousseau’s sign or carpopedal spasm (which may be found in primary hypomagnesemia with secondary hypocalcemia; see later discussion), tachycardia, and rarely athetoid and choreiform movements.
Infant patients are classically seen with partial seizures that have one or multiple foci. They are conscious and hyperactive. Diarrhea and secondary hypocalcemia are present.3 Seizures occur repeatedly and are resistant to antiepileptic drugs. Stiffness of all four extremities and hypertonia also have been reported.50 In children and adults, generalized tonic–clonic seizures associated with nonepileptic massive myoclonic jerks and carpopedal spasm, without diarrhea, were the presenting
symptoms.175 Sudden-onset aphasia and no clear initial motor seizure activity have also been reported.64
symptoms.175 Sudden-onset aphasia and no clear initial motor seizure activity have also been reported.64
Convulsions and diarrhea are intractable, and children may die if the magnesium disorder is not recognized and corrected early.3 Otherwise, the prognosis is relatively good with normal psychomotor development as long as magnesium supplements are maintained.
Diagnostic Evaluation
Hypomagnesemia should be strongly suspected in infants with generalized or partial seizures with one or multiple foci of unknown cause that are resistant to treatment and are associated with diarrhea and tetany that do not respond to calcium replacement. Given that older patients are less symptomatic, isolated magnesium malabsorption has to be investigated at any age. Finally, complete investigation of magnesium metabolism should also be considered in cases of idiopathic epilepsy because of reports91,193 concerning a direct correlation between low levels of serum magnesium and the frequency of seizures and status epilepticus in patients with idiopathic generalized epilepsies.
Intestinal malabsorption of magnesium is confirmed by markedly elevated fecal magnesium levels and low serum magnesium levels, even if serum magnesium concentrations do not reflect total body magnesium stores. A 24-hour urine collection and intravenous magnesium loading test for total body magnesium determination are very sensitive. When facilities for serum magnesium determinations are not available, a trial of parenteral magnesium sulfate may serve as a therapeutic test if renal function is not impaired. Comprehensive intestinal and renal investigations to detect intestinal malabsorption and renal failure or tubulopathy, hormone and electrolyte determinations to detect hypoparathyroidism, hyperaldosteronism, and conditions associated with hypokalemia or hypocalcemia, and X-ray of the carpal bones to detect other metabolic diseases are also required.
In addition, because of the associated movement disorders, specific investigations to detect disease of the basal ganglia (computed tomography, magnetic resonance imaging, neurophysiologic evaluations, and laboratory tests for liver disease, metabolic disorders, and immunologic disease) should be considered.
Treatment
Elective therapy in isolated magnesium malabsorption consists of high-dose oral or parenteral magnesium supplements. Typically, magnesium administration alone controls convulsions and low serum levels of magnesium and calcium in primary hypomagnesemia; administration of calcium and vitamin D is not effective. The major complication of magnesium supplementation appears to be diarrhea caused by the magnesium itself.
Renal Failure
Renal failure leads to disturbances in the function of every organ system in the body. Complications of renal failure become increasingly prevalent as the glomerular filtration rate decreases below 5 mL/min/1.73 m2, the level of function that defines end-stage renal disease. Neurologic disorders remain an important source of morbidity and mortality in this vulnerable patient population. With the introduction of dialysis and renal transplantation, the spectrum of neurologic complication has changed. On one hand, the incidence and severity of uremic encephalopathy, neuropathy, and myopathy have declined.40 On the other hand, dialytic regimen or renal transplantation may determine neurologic disorders such as dialysis dementia, dialysis dysequilibrium syndrome, cerebrovascular accident, and hypertensive encephalopathy, which are thought to be the consequence of ultrafiltration-related arterial hypotension directly related to dialysis. Moreover, hemorrhagic stroke, subdural hematoma, osmotic myelinolysis, opportunistic infections, intracranial hypertension, Wernicke encephalopathy and peripheral neuropathy can also occur. In patients who undergo renal transplantation, immunosuppressive drugs may cause encephalopathy, movement disorders, opportunistic infections, neoplasms, myopathy, and atherosclerosis. The neurologic manifestations of renal failure are summarized in Table 2.
Table 2 Neurologic manifestations of renal failure | |
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This section discusses epileptic seizures in uremic encephalopathy, aluminum encephalopathy in infancy and childhood, dialysis disequilibrium syndrome, and dialysis encephalopathy syndrome.
Neurologic Manifestations of Uremia
Uremic Encephalopathy
General Findings.
Uremia can be defined as “systemic intoxication caused by severe glomerular deficiency associated with disturbances in tubular and endocrine functions of the kidney. It is characterized by retention of toxic metabolites derived mainly from proteins associated with changes in volume and electrolyte composition of the body fluids and excess or deficiency of various hormones.”35 The pathophysiology of uremic encephalopathy is complex and poorly understood. Renal failure results in a gradual accumulation of several substances, but no single metabolite has been identified as the sole cause of uremic encephalopathy.204 Accumulation of urea, uric and hippuric acids, phenols and conjugates of phenols, phenolic and indolic acids, glucuronic acid, various amino acids, polyamines, polypeptides, carnitine, sulfates, phosphates, and “middle molecules” has been observed.61 It may also depend on guanidino compounds; acidosis; hyperhydration and dehydration; electrolyte disorders (hyponatremia, hypomagnesemia, hypocalcemia, hyperkalemia); hormonal disturbances (parathyroid hormone, thyrotropin, prolactin, luteinizing hormone, growth hormone, insulin, and glucagon); disturbances of cerebral amino acid metabolism; decreased concentration of γ-aminobutyric acid (GABA); increased concentrations of dopamine and serotonin; diminished cerebral uptake of glutamine, valine, and isoleucine; and increased extraction of glycine and cystine.38 Seizures may be related to hypertension, electrolyte imbalance, aluminum toxicity, drug toxicity, and infections. Inhibition of cerebral sodium-potassium adenosine triphosphatase (ATPase) has been demonstrated in experimental animals, which might be correlated with elevation of intracellular sodium and seizure activity.142 A main role is thought to be played by guanidino compounds such as
methylguanidine and guanidinosuccinic acid, which were found to be highly increased in cerebrospinal fluid (CSF) and brain of uremic patients.61 They may also induce a disorder similar to the “twitch-convulsive” syndrome, including epilepsy.144 Activation of the excitatory NMDA receptors and concomitant inhibition of inhibitory GABAA-ergic neurotransmission have been pointed out as underlying mechanisms.61 Intrahippocampal guanidinosuccinic acid injection in unanesthetized rats triggered partial clonic seizures leading to generalized tonic–clonic seizures and eventually status epilepticus.158 Moreover, inhibition of cerebral sodium-potassium-ATPase was shown in experimental uremic animals.42 This might correlate with the elevation of intracellular sodium and might therefore be associated with the epileptogenicity affecting this population.40 In this context, the pathophysiologic role of parathyroid hormone should also be considered. Although the mechanisms are unknown, parathyroid hormone is able to facilitate the entry of calcium in brain tissue.42 Because calcium is an essential mediator of neurotransmitter release and plays a major role in intracellular metabolic and enzymatic processes, alterations in brain calcium may possibly take part in determining cerebral dysfunction and seizures. Focal or multifocal and stimulus-sensitive myoclonus is supposed to originate in the brainstem reticular formation.49 Uremic encephalopathy is reversible on correction of renal insufficiency, consistent with the failure of histopathologic studies to find a specific anatomic lesion.156
methylguanidine and guanidinosuccinic acid, which were found to be highly increased in cerebrospinal fluid (CSF) and brain of uremic patients.61 They may also induce a disorder similar to the “twitch-convulsive” syndrome, including epilepsy.144 Activation of the excitatory NMDA receptors and concomitant inhibition of inhibitory GABAA-ergic neurotransmission have been pointed out as underlying mechanisms.61 Intrahippocampal guanidinosuccinic acid injection in unanesthetized rats triggered partial clonic seizures leading to generalized tonic–clonic seizures and eventually status epilepticus.158 Moreover, inhibition of cerebral sodium-potassium-ATPase was shown in experimental uremic animals.42 This might correlate with the elevation of intracellular sodium and might therefore be associated with the epileptogenicity affecting this population.40 In this context, the pathophysiologic role of parathyroid hormone should also be considered. Although the mechanisms are unknown, parathyroid hormone is able to facilitate the entry of calcium in brain tissue.42 Because calcium is an essential mediator of neurotransmitter release and plays a major role in intracellular metabolic and enzymatic processes, alterations in brain calcium may possibly take part in determining cerebral dysfunction and seizures. Focal or multifocal and stimulus-sensitive myoclonus is supposed to originate in the brainstem reticular formation.49 Uremic encephalopathy is reversible on correction of renal insufficiency, consistent with the failure of histopathologic studies to find a specific anatomic lesion.156
Clinical Description.
Uremic encephalopathy almost invariably complicates both chronic and acute uremia, its severity depending on the rate of renal failure. Neurologic manifestations of acute and chronic renal failure do not differ qualitatively, but clinical symptomatology is usually more severe and progresses more rapidly in patients with an acute deterioration of renal function.42 The clinical course is characterized by variability from day to day. Presenting symptoms may be subtle and represented by apathy, irritability, inattentiveness, clumsiness, and fatigue. Tests show that attention span is impaired at this stage.42 “Frontal lobe” dysfunction manifests with deficient abstract thinking, behavioral disorders, paratonia, and palmomental reflex.42 Recent memory deficits indicate a more advanced stage of disease. Later, remote memory fails, and confusion, lethargy, stupor, and ultimately coma develop. Typical features of delirium (toxic psychosis), such as hallucinations, agitation, confusion, and disorientation, are especially frequent in acute renal failure. Mental impairment is greater in children who experience onset of chronic renal failure during the first year of life, especially within the first 2 months.166 Psychomotor and mental development are delayed, and a small head circumference and progressive decrease in IQ may be encountered, even in the absence of neurologic signs.4 Even in patients who have been treated with renal replacement therapy, memory deficits and sleep disturbances are not uncommon. Neuropsychological investigations showed significant deviation from normal controls in areas of attention/response speed, learning and memory, and perceptual coding.42 Movement disorders and epilepsy constitute a very characteristic clinical feature of uremic encephalopathy and define the so-called “uremic twitch-convulsive” syndrome,2 which consists of intense asterixis and multifocal myoclonic jerks that are accompanied by fasciculations, muscle twitches, and seizures.60 Early manifestations include muscle cramps, tremors, and asterixis. Muscle fasciculations and myoclonus appear in advanced encephalopathy. Asterixis or “flapping tremor” is probably caused by sudden loss of tonus, originating from cortical dysfunction and clinically consists of multifocal action-induced jerks that can even mimic drop attacks in severe cases. In uremia, both spontaneous action myoclonus and stimulus-sensitive myoclonus with good response to benzodiazepines can occur. Uremic myoclonus may be caused by a dysfunction in the lower brainstem reticular formation due to water-electrolyte imbalance leading to microcirculatory and degenerative changes.40 Thiamine deficiency is thought to determine chorea by interfering with basal ganglia function.106 “Alternating hemiparesis” can occur in up to 45% of patients.42
Epileptic seizures have been reported in about one third of patients with uremic encephalopathy. In cases of chronic renal failure, they are most often a late manifestation and sometimes a preterminal event.169 In acute renal failure, seizures occur within the first 15 days of disease.60 Late-onset seizures have been rarely observed in association with hemiparesis and transient blindness as a result of a posterior reversible encephalopathy syndrome.34 Usually, seizures are generalized tonic–clonic or myoclonic, but focal motor seizures and even epilepsia partialis continua have also been reported.60 Nonconvulsive status epilepticus characterized by acute confusion or stupor without motor seizures has also been observed in patients with end-stage renal failure.53
Neurophysiologic Investigations.
The EEG is abnormal in the setting of acute encephalopathy due to renal failure. EEG background activity becomes progressively disorganized. Decreased alpha activity is associated with the appearance of intermittent paroxysmal bursts of bilaterally synchronous slow waves, with largest amplitudes over the frontal regions (projected rhythm). In chronic renal failure, changes are less dramatic. As the uremic state progresses, the EEG becomes slower, with a recognizable correlation between the percentage of frequencies <7 Hz and the increase in creatinine. Bilateral spike and wave complexes, in the absence of evident clinical seizure activity, have been reported in up to 14% of patients with chronic renal failure.42 A paradoxical response to eye opening and an abnormal arousal response to afferent stimuli consisting of bursts of slow waves may occur. Photic driving, photomyogenic response, and photosensitivity manifested by paroxysmal epileptiform discharges are more characteristic of uremic encephalopathy. They may be elicited just before the onset of convulsions. Electroencephalographic features correlate with alteration in consciousness to a greater degree than with the degree of uremia, electrolyte imbalance, and acidosis.185 Asterixis is electromyographically characterized by typical silence, which follows a biphasic wave in the backaveraged EEG activity.
The N75 and P100 components of one visual-evoked potential (VEP) are significantly prolonged in chronic renal failure.57 Peak V and I–V and III–V interpeak latencies of brainstem auditory-evoked responses (BAERs) were significantly prolonged in one third of chronic renal failure patients.176 Unfortunately, no significant correlations have been documented between the degree of prolongation of various VEP or BAER component latencies and the severity of chronic renal failure or its associated metabolic complications.
Visually-evoked event-related potentials (ERPs) in neurologically asymptomatic patients affected by chronic renal failure clearly showed an increased P3 latency and decreased P3 amplitude. After hemodialysis, P3 latency showed a significant decrease, and P3 latency habituation during the ERP measurement was also significantly decreased. These data suggested that impaired cognitive processing can be disclosed by ERP even in neurologically asymptomatic chronic renal disease. Removal of uremic toxins by hemodialysis leads to an improvement in cognitive function.73
Somatosensory-evoked potentials (SEPs) after median nerve stimulation are enhanced bilaterally. Both the biphasic wave and the giant SEP are believed to have a common origin in the sensorimotor cortex in brain-mapping recordings.22
Diagnostic Evaluation.
A combination of clinical signs of depression and signs of cerebral excitation, such as multifocal myoclonus and epilepsy, is strongly suggestive of uremia.
When seizures are present, a series of investigations, including determination of bone and plasma aluminum concentrations and plasma and urinary electrolyte concentrations, osmolality, volume, and levels of ADH, has to be performed to exclude other, superimposed causes of seizures, such as hypertensive encephalopathy, electrolyte imbalance (water intoxication, hypocalcemia, hyponatremia, hypomagnesemia), or aluminum encephalopathy. Computed tomography followed by lumbar puncture (unless intracranial pressure is increased), which may show elevated protein concentrations or pleocytosis, can aid in the diagnosis of infection of the central nervous system. Papilledema, focal neurologic signs, and elevated opening pressure at lumbar puncture may suggest hypertensive encephalopathy or intracranial hemorrhage. If no causes are demonstrated, an idiopathic seizure disorder must be differentiated. When a patient with acute or chronic renal failure experiences an unexpected onset of seizures, asterixis, myoclonus, and behavioral disturbances such as agitation and confusion (toxic psychosis), a drug-induced encephalopathy should be suspected. In the case of renal failure, the availability of certain drugs, such as vigabatrin, acyclovir, chlorpromazine, cyproheptadine, salicylates, phenytoin, barbiturates, and benzodiazepines or their metabolites, is increased by the diminished urinary elimination of active metabolites or diminished protein binding, which increases their plasma concentrations. Immunosuppressive-associated encephalopathy has been described with cyclopsorin,51 tacrolimus,161 and muromonab-CD3.159 The clinical picture involves tremor, cerebellar and and/or extrapyramidal signs, and headache. Sometimes a reversible posterior leukoencephalopathy syndrome may complicate the clinical course,161 with white matter changes. Subcortical and cortical involvement has also been described.31 Recognition of immunosuppressant-associated encephalopathy is crucial because modulation in immunosuppressive drugs administration may result in resolution of clinical symptoms and neuroimaging abnormalities.
Finally, possible thyroid disorders have to be investigated (see section on endocrine disorders). Video-polymyographic-EEG recordings and electromyographic (EMG) examinations must be performed to differentiate epileptic events from other, nonepileptic movement disorders such as asterixis, tremor, and myoclonus.
Treatment.
Clinical symptoms of uremic encephalopathy may improve following dialysis and renal transplantation. The development of uremic encephalopathy is an indication for prompt initiation of dialysis and consideration of renal transplantation.
Seizures may be treated with standard antiepileptic drugs, taking into account the changes in renal excretion and reductions in plasma protein binding that may occur in renal insufficiency. Therefore, monitoring of blood levels of drugs is advisable; levels of unbound antiepileptic drugs, which increase during renal disease, are most informative. In general, oral doses of all the antiepileptic drugs should be reduced and the intervals of administration modified. Sodium and magnesium valproate and phenytoin free plasma fractions increase, whereas lamotrigine clearance is not significantly modified in renal disease. Carbamazepine (which may exert a significant antidiuretic effect, causing increased danger of fluid retention), vigabatrin, and felbamate (which are excreted almost entirely by the kidneys) should not be given.129 Benzodiazepines, and especially clonazepam, are effective against myoclonus,4 whereas piracetam and l-5-hydroxytryptophan cannot be used in renal failure. Sedative hypnotics and antipsychotic tranquilizers, which may cause toxic psychosis,122 and antibiotics, which may induce myoclonus, asterixis, seizure, and coma, must be administered with extreme care.172 With respect to the newer antiepileptic drugs, zonisamide and oxcarbazepine are cleared by both the renal and hepatic routes. The clearance of both drugs has been shown to decrease with decreasing creatinine clearance. No specific guidelines for dose adjustment have been provided for zonisamide. Oxcarbazepine should be initiated at one half of the usual starting dose and increased to achieve clinical response.41,128 More than two thirds of levetiracetam and topiramate is excreted in the urine. A reduction in the dosing rate for both drugs is recommended for patients with moderate or severe renal impairment.41
Aluminum Encephalopathy Syndrome in Infancy and Childhood
General Findings.
Aluminum encephalopathy syndrome is a progressive encephalopathy that tends to occur in infants and children with chronic renal failure following prolonged exposure to aluminum-containing solutions and compounds, such as aluminum-containing phosphate binders.165 It has also been described in adults.177 Although the mechanisms for the entry of aluminum into the central nervous system (CNS) are poorly understood,174 the aluminum content of brain gray matter of these patients has been found to be markedly elevated in comparison with controls.6 It has mainly been found in the nerve cells of the cerebral cortex.6 Neuropathologically, the brain shows cortical atrophy and stromal spongiosis.190 The mechanisms associated with the pathogenesis of the neurotoxicity of aluminum are unknown.174 The increased bioavailability of aluminum in chronic renal failure seems to be related to decreased urinary excretion and enhanced gastrointestinal aluminum uptake induced, in turn, by secondary hyperparathyroidism, which is common in infants and children with chronic renal failure. Aluminum in individuals with chronic renal failure is stored in bone tissue, from which it may be mobilized during intercurrent stress, thereby causing acute aluminum intoxication.
Clinical Description.
Usually, aluminum encephalopathy syndrome develops in children with chronic renal failure who have been exposed to aluminum for several years. Clinically, aluminum encephalopathy syndrome is closely similar to both uremic encephalopathy and dialysis dementia syndrome. Features are a progressive encephalopathy with arrest or regression of psychomotor development, disturbances of motor function (such as dysmetria, tremor, hypotonia, focal or generalized myoclonus), seizures, speech disturbances, and ultimately vegetative status. Seizures are usually generalized, but simple and complex partial seizures with secondary generalization have also been reported.177 Subacute aluminum encephalopathy with loss of consciousness, myoclonic jerks, and status epilepticus leading to the exitus was related to the direct exposure of CNS to aluminum.170 Computed tomography shows cortical atrophy. Electroencephalographic features, which evolve simultaneously with clinical features, consist of diffuse slowing of background activity with superimposed bursts of high-amplitude slow waves and multiple paroxysms of triphasic contoured waves, sharp waves, and complexes of spikes and slow waves.103
Diagnostic Evaluation.
The presence of typical clinical features in children with chronic renal failure who have been taking aluminum-containing phosphate binding gels or formulas suggests aluminum encephalopathy syndrome. Computed tomography showing cortical atrophy, presence of specific EEG features, and demonstration of high bone and plasma aluminum concentrations confirm the diagnosis. Aluminum encephalopathy syndrome has to be differentiated from uremic encephalopathy, which also causes mental retardation, myoclonus, and seizures. This differential diagnosis is very important because uremic encephalopathy promptly improves with dialysis, whereas aluminum encephalopathy syndrome does not in all cases. Electrolyte determinations may differentiate aluminum encephalopathy syndrome from
acute hypercalcemia, severe phosphate depletion, and other electrolyte imbalances that may complicate chronic renal failure. Finally, aluminum encephalopathy syndrome must be differentiated from the rare cases of aluminum intoxication in nonuremic patients.102,174 Video-polymyographic-EEG recordings and EMG examinations are mandatory in the differential diagnosis of movement disorders, such as asterixis, tremor, and myoclonus, and other epileptic events.
acute hypercalcemia, severe phosphate depletion, and other electrolyte imbalances that may complicate chronic renal failure. Finally, aluminum encephalopathy syndrome must be differentiated from the rare cases of aluminum intoxication in nonuremic patients.102,174 Video-polymyographic-EEG recordings and EMG examinations are mandatory in the differential diagnosis of movement disorders, such as asterixis, tremor, and myoclonus, and other epileptic events.
Treatment.
Prompt discontinuation of the use of aluminum gels is indicated. Dramatic improvement in advanced stages has been achieved by aluminum chelation (deferoxamine). The combined use of deferoxamine and appropriately timed hemodialysis has been proposed in the rare patients presenting with severe acute aluminum intoxication.147 Common antiepileptic drugs and especially benzodiazepines are effective in the treatment of myoclonus and seizures, but the same risks are encountered as in the treatment of uremic encephalopathy (see earlier discussion). Because the main cause of aluminum encephalopathy syndrome is gastrointestinal absorption of aluminum, infant diets should consist of low-phosphate formulas with the addition of calcium carbonate. Calcium citrate– and aluminum-containing antacids should be avoided.
Neurologic Complications of Uremia Treatment
Dialysis Dysequilibrium Syndrome
General Findings.
Dialysis dysequilibrium syndrome is an acute reversible neurologic syndrome caused by exacerbation of the neurologic manifestations of renal failure during a patient’s first few dialysis maintenance treatments. Dialysis disequilibrium syndrome has been attributed to the “reverse urea effect” during rapid hemodialysis. Urea is believed to be cleared less rapidly from the brain than from the blood, producing an osmotic gradient and shift of extracellular water into the brain to cause cerebral edema.115 Experimental data showed a reduced expression of urea transporter (UT-B) and increased expression of aquaporins in brain cells. Urea exit from astrocytes is therefore delayed during rapid removal of extracellular urea through fast dialysis. An osmotic driving force that promotes water entry into the cells is also favored by abundant expression of aquaporins.203 Moreover, it has been demonstrated that cerebral edema may result from the generation of idiogenic osmoles in association with a decrease in intracellular pH of the cerebral cortex.
Clinical Description.
The symptoms of dialysis dysequilibrium syndrome are irritability, restlessness, headache, nausea, emesis, hypertension, blurred vision, epileptic seizures, muscular twitchings, fasciculations, asterixis, and confusion. Seizures usually are generalized tonic–clonic, and status epilepticus may also occur.189 When delirium appears, it tends to persist for several days. Death from brainstem herniation has been reported in the past, while in more recent years only milder symptoms have been reported. After a general trend toward normalization, marked EEG changes may develop during dialysis, consisting of increased slow-wave activity, bursts of bilateral symmetric rhythmic slow waves, and increased photosensitivity.185 Patterns of VEPs are exaggerated, with abnormal prolongation of P100;57 BAER latencies are abnormal.176 Computed tomography demonstrates cerebral edema. Brain magnetic resonance imaging (MRI) may show white matter changes in the posterior area mimicking a reversible posterior leukoencephalopathy syndrome (RPLS).189 Central pontine and extrapontine myelinolysis has also been reported in children.25
Diagnostic Evaluation.
Diagnostic evaluation must exclude all other causes of irritability, headache, nausea, hypertension, muscular twitchings, fasciculations, asterixis, confusion, and seizures that can occur in patients on maintenance dialysis. Seizures are a key symptom. When seizures occur with various degrees of impairment of consciousness, headache, nausea and vomiting, hypertensive encephalopathy, intracranial hemorrhage, and subdural hematoma127 should be investigated. Papilledema, focal neurologic signs, typical findings on computed tomography, and elevated opening pressure at lumbar puncture confirm the diagnosis of these conditions. When seizures are generalized or partial and are associated with irritability, headache, restlessness, or twitchings, special consideration must be given to disorders of electrolyte imbalance, including hyponatremia and hypernatremia (which in renal insufficiency may induce seizures more frequently than hyponatremia), hypocalcemia and hypercalcemia, hypophosphatemia, abrupt increase in blood pH (which can lower the serum concentration of ionized calcium), and nonketotic hyperosmolal coma in nondiabetic patients, which is caused by increasing levels of glucose after repeated peritoneal dialysis. Determination of plasma and urinary electrolyte concentration, glucose concentration, osmolality, volume, ADH levels, and presence of acidemia may aid in the differential diagnosis. Full neurophysiologic monitoring is useful to differentiate epileptic myoclonus and seizures from other, nonepileptic movement disorders and detect any sudden changes of central nervous system electrical activity during dialysis.
Treatment.
If a patient experiences seizures during dialysis, treatment must be discontinued immediately until vital signs have stabilized. Standard therapy of movement disorders and epileptic seizures may improve the patient’s course but must be monitored carefully in renal failure (see earlier discussion of treatment of uremic encephalopathy). Hypocalcemic seizures may be controlled with calcium gluconate administration.
Dialysis Encephalopathy Syndrome
General Findings.
Dialysis encephalopathy syndrome has been described in patients receiving maintenance hemodialysis. The syndrome usually occurs in patients dialyzed for periods >3 years. It is considered to be the most dramatic manifestation of aluminum toxicity, and is caused by an increase in brain levels of aluminum secondary to a high content of this metal in the dialysis bath.6 Its incidence has sharply decreased with the use of aluminum-free water.4
Clinical Description.
Presenting symptoms consist of dysarthria, apraxia, and slurred speech with stuttering and hesitation. The speech disorder is intensified during and immediately after dialysis and at first may be seen only during these periods. Cognitive disturbance usually occurs, and the EEG shows bursts of high-amplitude slow waves in the frontal regions. Within months, myoclonus, asterixis, movement dyspraxia, seizures, memory loss, personality changes, and psychosis develop.78 In most cases, the disease progresses to apneic spells, tonic–clonic seizures, focal neurologic deficits, and death within months from sepsis or suicide.6
After a short and transient improvement, usually following dialysis, the EEG shows progressive abnormalities that become indistinguishable from those seen in aluminum encephalopathy syndrome (see earlier discussion).185
Diagnostic Evaluation.
Dysarthria, myoclonus, delirium, and seizures are possible symptoms of clinical conditions that may exist concomitantly with hemodialysis, such as acute hypercalcemia173 and severe hypophosphatemia,164 and these must be differentiated from dialysis encephalopathy syndrome. Video-polymyographic-EEG recordings and EMG examinations must be performed to differentiate epileptic myoclonus from other, nonepileptic movement disorders.105 Water-soluble vitamin deficiency, especially pyridoxine deficiency (removed from blood during hemodialysis), should always be considered
in cases of drug-resistant seizures. Clinical and EEG features similar to those of dialysis encephalopathy syndrome have been described in patients not on dialysis who are receiving large quantities of aluminum salts.187 The CSF is unremarkable. No distinct abnormalities have been found in brain at autopsy. In all these cases, only the history and laboratory investigations may aid in the differential diagnosis.
in cases of drug-resistant seizures. Clinical and EEG features similar to those of dialysis encephalopathy syndrome have been described in patients not on dialysis who are receiving large quantities of aluminum salts.187 The CSF is unremarkable. No distinct abnormalities have been found in brain at autopsy. In all these cases, only the history and laboratory investigations may aid in the differential diagnosis.
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