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decreased serum anion gap, hemodialysis may be required for severe intoxication.339

Many other drugs are proconvulsive and may produce seizures, as indicated in Table 5–17.

Ethanol Intoxication

One would hardly think that it takes a medical education to diagnose a drunk, but the appraisal of ethanol intoxication sometimes turns out to be deceptively difficult. In Belfast, for example, where events should provide no lack of experience, the diagnosis of alcohol or nonalcohol ingestion in patients with head injury was incorrectly made a full 12% of the time. Of even greater potential consequence, six of 42 subjects with blood levels over 100 mg/dL were clinically unrecognized as being intoxicated.341

Alcohol exerts its main sedative effect by potentiating the GABAA receptor. However, it also affects other neurotransmitters, including causing increases in dopaminergic transmission, which is a critical component of the reward system to the brain. It also promotes the release of noradrenaline, blocks the NMDA glutamate receptor, and stimulates the 5HT3 receptor.342

Moderately large doses of ethanol represent a frequent cause of stupor, most examples of which recover spontaneously without medical attention. Large doses produce a coma that at greater than 400 mg/dL can be fatal, primarily due to respiratory depression. A major problem with alcohol ingestion is that the ensuing uninhibited behavior leads to the impulsive ingestion of other sedative, hypnotic, or antidepressant drugs or to careless, headstrong, and uncoordinated activity (e.g., fighting, driving while intoxicated) that invites head trauma. As a result, the major diagnostic problem in altered states of consciousness associated with acute alcoholic intoxication lies in separating the potentially benign and spontaneously reversible signs of alcoholic depression from evidence of more serious injury from other drugs or head trauma.

As noted above, in pure alcohol intoxication, blood levels correlate fairly well with clinical signs of intoxication. Dose levels correlate less well because the rate of absorption from the stomach and intestine depends heavily on the presence or absence of other stomach con-

tents. Chronic ingestion induces moderate tolerance, but in general, the associations in Table 5–16 represent dependable guidelines. When estimating dosage, the physician should recall that in the United States the alcoholic content of distilled spirits equals 50% of the stated proof on the label.

Clinical signs of acute drunkenness can closely resemble those caused by several other metabolic encephalopathies, especially including other depressant drug intoxication, diabetic ketoacidosis, and hypoglycemia. Innate psychologic traits influence the behavior of many drunks, adding to the complexities of diagnosis. As mentioned above, the odor of the breath depends on impurities and is an unreliable sign. Patients with alcohol intoxication are ataxic, clumsy, and dysarthric. They are easily confused, are often uninhibited and boisterous (or, more severely, stuporous), and commonly vomit. The conjunctivae are often hyperemic and with severe poisoning the pupils react sluggishly to light. Severe intoxication or stupor produces a remarkable degree of analgesia (‘‘feeling no pain’’) to noxious stimuli such that prior to the discovery of modern anesthetics, alcohol was often used for this purpose.

Table 5–16 Clinical Effects and

Blood Levels in Acute Alcoholism

Anesthesia

Stertor, hypoventilation

Coma

A secure diagnosis of alcoholic intoxication and its severity requires blood level determinations. When these are unavailable, determining serum osmolality helps.324 Alcohol adds osmols to blood in a degree proportional to its blood level. A blood level over 150 mg/dL produces a serum osmolality of less than 320 mOsm/kg, and patients with blood alcohol levels of 200 mg/dL had a serum osmolality of greater than 340 mOsm/kg. Because alcohol is uniformly distributed in body water, the hyperosmolality does not lead to fluid shifts out of the brain, and thus, the hyperosmolality produced by alcohol is not in itself a cause of symptoms.

Intoxication With Drugs of Abuse

Party or club drugs include GHB, ketamine, Rohypnol (flunitrazepam), methamphetamine, lysergic acid diethylamide (LSD), and 3,4-

methylenedioxymethamphetamine (MDMA; Ecstasy).322,343 Other drugs include cocaine,

opioids (see above), and phencyclidine. These drugs may be taken alone or in combination and can cause critical illness.327

Cocaine may be taken nasally, orally, or intravenously. The drug inhibits neuronal uptake of catecholamines and causes CNS stimulation. Patients are often euphoric and may be anxious, agitated, and delirious, and sometimes have seizures. Agitation can be controlled with benzodiazepines. Some patients are febrile and require cooling. There is no specific antidote. Some patients develop a CNS vasculitis that can result in cerebral infarction, myocardial infarction, and sometimes cerebral hemorrhage. This is currently one of the most common causes of stroke in young adults without the usual risk factors for atherosclerotic disease.

GHB causes a state of deep sleep with highvoltage delta EEG. It has been released in the United States to treat narcolepsy, in which fragmented sleep at night contributes to daytime symptoms such as cataplexy. Because it induces such deep unresponsiveness, it has achieved a reputation as a date rape drug344 and, at high doses, can cause coma and respiratory insufficiency. It has a rather short halflife, so that recovery usually occurs within several hours. Some uncontrolled studies have suggested physostigmine as an antidote, but

the evidence for this is poor and experimental studies have failed to find an effect.345,346

Phencyclidine, or ‘‘angel dust,’’ is a glutamate NMDA receptor antagonist.347 It results in bizarre behavior and agitation and, at higher doses, can produce delirium and coma. Both vertical and horizontal nystagmus are common. Seizures and dystonic reactions are less common. Many patients have pinpoint pupils when they are awake and agitated, and this can be a clue to the diagnosis. Patients may develop hypertensive encephalopathy; intracranial and subarachnoid hemorrhages have been reported. Ketamine, another NMDA antagonist, has been used as an anesthetic agent and is still used in the veterinary setting.348 As a club drug it can either be ingested or smoked. It causes delirium, often with hallucinations. Side effects may include hypothermia and respiratory depression.349 With either drug, a benzodiazepine may help control violent behavior.327

MDMA has its major effect on the serotonin system. It is an indirect serotonin agonist that inhibits tryptophan hydroxylase and thus decreases serotonin production. It also induces the release of serotonin and blocks serotonin reuptake. The drug also increases the release of dopamine and norepinephrine from presynaptic neurons and prevents their metabolism by inhibiting monamine oxydase. The usual adverse effects include anxiety, ataxia, and difficulty concentrating; seizures can occur and pupillary dilation is common. Hyperthermia may lead to death.349 Agitation and seizures can be treated with benzodiazepines.

Flunitrazepam (Rohypnol) is a benzodiazepine and like other drugs in this class potentiates GABAA receptors. Its effects are similar to other drugs in this class, such as benzodiazepines or alcohol intoxication, except that it is more likely to produce respiratory depression, so that overdose can be life threatening. Flumazenil, a benzodiazepine antagonist, can reverse the toxicity.349

Intoxication With Drugs Causing

Metabolic Acidosis

The metabolism and mechanisms of neurologic changes in acid-base disorders are discussed on pages 188–192. This section considers specific exogenous poisons causing metabolic acidosis.325 These include methyl alcohol,

ethylene glycol, and paraldehyde. Salicylate poisoning also produces a metabolic acidosis in the tissues, but in adults this aspect of the disorder often is overshadowed in the blood by evidence of respiratory alkalosis.

The metabolic acidosis and neurotoxicity of methyl alcohol, ethylene glycol, and paraldehyde all result from their metabolic breakdown products rather than the original agent. Poisoning from all three drugs is most common in chronic alcoholics who ingest the agents either by mistake or in ignorance of their risks as a substitute for ethanol. All three agents initially cause symptoms of alcohol intoxication, progressing to confusion and stupor, by which point symptoms and signs of severe acidosis and systemic organ complications usually emerge as well.

Methanol is degraded by alcohol dehydrogenase into formic acid.327 The presence of ethanol in the system slows its metabolic breakdown, thereby influencing the clinical course. The earliest and most frequent neurologic damage of methyl alcohol poisoning affects retinal ganglion cells. The symptoms of methanol poisoning can evolve over several days or appear abruptly. Stupor, coma, or seizures occur only in severely poisoned patients. Most subjects at first give the appearance of advanced inebriation and develop visual loss (‘‘blind drunk’’). Hyperpnea (respiratory compensation for metabolic acidosis) is the rule. Effective early intervention depends on recognizing the presence of an organic acidosis and treating it vigorously by using an inhibitor of alcohol dehydrogenase, such as fomepizole.24 Because ethanol competes with methanol for alcohol dehydrogenase and thus slows its metabolism, it may be used to minimize the damage from methanol if a specific inhibitor is not readily available. If these drugs fail, hemodialysis may be indicated.327 The following patient illustrates the point.

Patient 5–19

A 39-year-old man had been intermittently drinking denatured alcohol for 10 days. He was admitted complaining that for several hours his vision was blurred and he was short of breath. He was alert, oriented, and coherent, but restless. His blood pressure was 130/100 mm Hg, his pulse was 130 per minute, and his respirations were 40 per

minute, regular and deep. The only other abnormal physical findings were 20/40 vision, engorged left retinal veins with pink optic disks, and sluggishly reactive pupils, 5 mm in diameter. His serum bicarbonate level was 5 mEq/L, and his arterial pH was 7.16. An intravenous infusion was begun immediately; 540 mEq of sodium bicarbonate was infused during the next 4 hours. By that time his arterial pH had risen to 7.47 and his serum bicarbonate to 13.9 mEq/L. He was still hyperventilating but less restless. The infusion was continued at a slower rate for 20 hours to a total of 740 mEq of bicarbonate. He recovered completely.

Comment: Denatured alcohol, usually sold as a solvent, contains about 83% ethanol and 16% methanol. Hence, it is not unusual for alcoholics to ingest denatured alcohol, despite the required warnings on the label, and this source should be sought in the emergency department when a patient who appears intoxicated with ethanol complains of visual symptoms and is hyperventilating. It is likely that the presence of ethanol sufficiently slowed the metabolism of methanol in this patient so that he was able to recover. This patient had profound acidosis, as was reflected by the requirement of 540 mEq of parenteral sodium bicarbonate to raise his serum bicarbonate from 5 to 13 mEq/L. However, it is not clear that bicarbonate therapy improves outcome.325 Some patients suffer from hypercalcemia and hypoglycemia, and these need to be corrected. Patients may be chronically malnourished and treatment with vitamins, particularly thiamine but also folate and pyridoxine, should be administered. These same general guidelines apply to ingestion of other alcohols as indicated below. The acidosis of methyl alcohol poisoning can be lethal with alarming rapidity. One of our patients walked into the hospital complaining of blurred vision. He admitted drinking ‘‘a lot’’ of methyl alcohol and was hyperventilating. During the 10 minutes that it took to transfer him to a treatment unit he lost consciousness. By the time an intravenous infusion could be started, his breathing and heart had stopped and resuscitation was unsuccessful. No bicarbonate could be detected in a serum sample drawn simultaneously with death.

Paraldehyde is no longer available in the United States, as it has been replaced by other drugs for treating status epilepticus, although it may still be available in other countries.350

Paraldehyde is metabolized to acetic acid, which may cause acidosis, but the degree of acidosis in these patients exceeds the amount of detectable acetic acid in the serum, implying the presence of other acid products as well. Distinctive clinical features, in addition to the manifestations of metabolic acidosis, include the odor of paraldehyde on the breath, abdominal pain, a marked leucocytosis, and obtunded, lethargic behavior. All patients reported to date have recovered.

Ethylene glycol (antifreeze) is metabolized by alcohol dehydrogenase, the end products being formic, glyoxylic, and oxalic acids.327 A relatively severe metabolic acidosis occurs during the early hours of toxicity. The initial clinical signs are similar to alcohol intoxication but without ethanol’s characteristic odor. Patients with severe poisoning go on to disorientation, stupor, coma, convulsions, and death. Neuroophthalmologic abnormalities including papilledema, nystagmus, and ocular bobbing can be prominent. Metabolic abnormalities, if uncorrected, can lead to cardiopulmonary failure. A late complication of ethylene glycol poisoning is renal damage caused by oxalate crystalluria. Diagnosis should be suspected by a history of ingestion of antifreeze in an alcoholic or after a suicide attempt, the identification of an anion gap metabolic acidosis, and the detection of characteristic oxalic acid crystals in the urine. The treatment is the same as that of methanol poisoning (see above).339

Propylene glycol is a widely available organic solvent used in a variety of oral and injectable pharmaceutical agents, food preparations, and cosmetic materials. Because of its typically pharmacologically inert nature, propylene glycol overdose is not considered in the differential diagnosis of acute large anion gap acidosis and is not included in standard toxicologic studies (or may be used as an internal standard masking overdose). However, propylene glycol overdose may produce profound CNS compromise including stupor and coma, cardiovascular collapse, and marked hematologic changes including leukocytosis, thrombocytosis, microcytic anemia, and bone marrow abnormalities. Animal studies indicate reduction in arousal following repeated intoxication, suggesting that long-term CNS depression results from chronic propylene glycol exposure.351 Commercial preparations of propylene glycol contain a racemic mixture and are metabolized in vivo to

both d- an l-lactic acid isomers. Cats that developed CNS depression were noted to accumulate d-lactate on a dose-dependent basis that was positively correlated with an elevated anion gap. Preferential accumulation in the brain is thought to occur because of the low level of catabolizing enzyme in this site. d-lactic acidosis is known to produce a toxic encephalopathy in humans, usually in the setting of short bowel syndrome.352

Lactic acidosis has emerged increasingly in recent years as a metabolic disorder sometimes associated with neurologic symptoms and a poor prognosis.353 Mild and asymptomatic elevations of serum lactate up to 6 mEq/L accompany a number of conditions including alkalosis, carbohydrate infusions, anxiety, and other conditions that elevate blood epinephrinemia, diabetic ketoacidosis, and alcohol intoxication. More intense, but still systemically benign, lactic acidosis with arterial blood levels of 20 mEq/L or more and blood pH levels below 7.00 can follow vigorous muscular exercise. We have observed similar degrees of acidosis and acidemia following major motor convulsions, but in neither exercise nor epilepsy was there evidence that the lactacidemia affected brain function. Lactic acid crosses the blood-brain barrier via a carrier mechanism that saturates at about three to four times the normal plasma concentration of 1 mEq/L. Thus, although high concentrations of lactate in the brain are believed to be neurotoxic, possibly by promoting excitotoxicity,354 these probably only occur when produced by local brain ischemia or in conditions in which systemic hypoxia, circulatory failure, or drug poisoning also affect directly the oxidative metabolism of the CNS.

In adults, salicylate intoxication appears in two principal forms. Relatively younger persons sometimes take aspirin or similar agents in suicide attempts. Although many become severely ill and a few die with terminal coma or convulsions, most of these younger patients lack prominent neurologic complaints except for tinnitus and dyspnea. Older persons, by contrast, often ingest salicylates in excessive amounts more or less accidentally in proprietary analgesics; in these patients, neurologic symptoms can dominate the early illness, producing an encephalopathy that initially obscures the etiologic diagnosis. Salicylates act as a ‘‘metabolic uncoupler’’ in oxidative phosphorylation and stimulate net organic acid production. Aspirin (acetylsalicylic

acid) also contains 1.7 mEq of acid per 300-mg tablet. In experimental animals, death from salicylate poisoning comes from convulsions and relates directly to the concentration of the drug in the brain; clinical evidence suggests that similar principles apply in humans.

Salicylates in adults stimulate respiration neurogenically to a degree that nearly always produces a respiratory alkalosis in the blood unless simultaneous ingestion of a sedative drug suppresses the respiratory response.327 The metabolic acidosis of the tissues is reflected usually by a disproportionately lowered serum bicarbonate and always by an acid urine. Depending on age, associated illness, and the rapidity of accumulation, the first symptoms of salicylate intoxication usually appear at a blood level of about 40 to 50 mg/dL. Blood levels over 60 mg/ dL usually produce symptoms of severe toxicity. Initial complaints are of tinnitus and, less often, deafness. As many as one-half of older persons with severe salicylate intoxication develop confusion, agitation, slurred speech, hallucinations, convulsions, stupor, or coma. Hyperpnea, intact pupillary responses, intact oculocephalic responses, diffuse paratonia, and, in many instances, extensor plantar responses are present. In a patient with metabolic encephalopathy, a respiratory alkalosis and mildly abnormal anion gap in the blood combined with aciduria are almost

Table 5–18 Selected Drugs and

Poisons With Specific Antidotes

Modified from Fabbri et al.,323 with permission.

always diagnostic of salicylism and can be quickly confirmed by determination of salicylate blood levels. Salicylate intoxication may be complicated by gastrointestinal bleeding, pulmonary edema, and multiorgan failure. Hemodialysis may be necessary to treat the disorder. The following patient illustrates the problem.

Patient 5–20

A 74-year-old woman with osteoarthritis, selftreated with aspirin, developed peptic ulcer disease. She was admitted to the hospital, where she was noted to be lethargic and confused after she fell out of bed. With a dysarthric, deepened voice, she complained of a recent loss of hearing. The examination showed fluctuating lethargy, asterixis, and bilateral extensor plantar responses, but little else. A CT scan was unremarkable and the changes were at first ascribed to the nonfocal effects of trauma. The next day, however, she was barely arousable, severely dysarthric, and disoriented when she did respond. The pupils were 2 mm and equal, the oculocephalic responses full and conjugate, and prominent bilateral asterixis involved the upper extremities. Both plantar responses were extensor and the respiratory rate was 32 per minute. Arterial blood gases were pH 7.48, PCO2 24 mm Hg, PO2 81 mm Hg, and HCO3 19 mEq/L. Serum sodium was 134, potassium 3.5, and chloride 96 mEq/L, giving an anion gap of approximately 19. Serum salicylate level was 54 mg/dL. She was treated cautiously with alkaline diuresis and became alert without abnormal neurologic symptoms or signs within 48 hours. Her aspirin was found in the bedside table.

Many poisons have specific antidotes, and some of the most common are indicated in Table 5–18.

ABNORMALITIES OF IONIC OR ACID-BASE ENVIRONMENT OF THE CENTRAL

NERVOUS SYSTEM

The term osmolality refers to the number of solute particles dissolved in a solvent. Osmolality is usually expressed as milliosmoles per liter

of water (mOsm/L). It can either be measured directly in the serum by the freezing point depression method or, for clinical purposes, calculated from the concentrations of sodium, potassium, glucose, and urea (the predominant solutes) in the serum (assuming that there is no intoxication). The formula below gives a rough but clinically useful approximation of the serum osmolality:

Sodium and potassium are expressed in mEq/L, and the divisors convert glucose and BUN expressed in mg/dL to mEq/L. If the glucose and BUN are normal, the serum osmolality can be approximated by doubling the serum Naþ and adding 10.

Normal serum osmolality is 290 ± 5 mOsm/ kg. As indicated on page 248, a measured osmolality higher than the calculated osmolality indicates a substantial concentration of an unmeasured osmolar substance, usually a toxin. Hypo-osmolality leads to an increased cellular water content and tissue swelling. Only a few agents are equally and rapidly distributed throughout the body water (e.g., alcohol); therefore, hyperosmolality due to excess ethanol does not affect water distribution within the brain. However, the blood-brain barrier prevents most agents from entering the CNS. As a result, hyperosmolality due to these agents results in redistribution of water from within the CNS to the circulation. This property is used clinically when mannitol (a nonmetabolizable sugar) is injected intravenously to draw fluid out of the brain and temporarily decrease cerebral edema. However, the brain has protective mechanisms against osmolar shifts,355 including slow redistribution of solutes, so that rapid changes in serum osmolality produce more prominent neurologic symptoms than slow changes. Direct measurement of osmolar substances using MRS demonstrates decreases

in myelinositol, choline, creatine, phosphocreatine, and probably glutamate/glutamine. Interestingly, in the patients studied who had chronic hyponatremia (mean serum sodium 120 mEq/L), there was no increase in water content.356 Accordingly, it is not possible to give exact values above or below normal at which symptoms will develop. However, subacute changes in serum osmolalities below about 260 mEq/L, or above about 330 mEq/L over hours or a few days, are likely to produce cerebral symptoms. In addition, cerebral symptoms can be produced by sudden restorations of osmolality toward normal when an illness has produced a sustained osmolar shift away from normal. In extreme cases, this can cause central pontine myelinolysis (page 171).

Hypo-osmolar States

Sodium is the most abundant serum cation, and for practical purposes, systemic hypoosmolarity occurs only in hyponatremic states. On the other hand, not all hyponatremic states are necessarily hypo-osmolar. For example, hyponatremia may be hyperosmolar, as with severe hyperglycemia (see page 171), or isoosmolar, as, for example, during transurethral prostatic resection when large volumes of sodium-free irrigants are systemically absorbed.

Hyponatremia or ‘‘water intoxication’’ can cause delirium, obtundation, and coma, examples being encountered annually in almost all large hospitals. Symptoms result from water excess in the brain, hence the name water intoxication (Figure 5–9A). The pathogenesis of the symptoms caused by hyponatremia is probably multifactorial.357,358 Water entering both neurons and glia causes brain edema and thus increased ICP. Brain herniation is probably the event leading to death. In an attempt to compensate, sodium and potassium are excreted from cells via a sodium-potassium

ATPase pump, altering membrane excitability359 and perhaps causing the seizures that are common in severe hyponatremia. Seizures may lead to hypoxia, but whether hypoxia plays a significant role in the development of the clinical symptoms is unclear.357

Although acute hyponatremia can be fatal, chronic hyponatremia is usually only mildly symptomatic. The reason appears to be that the brain adapts to the hyponatremia by decreas-

ing organic osmols within the cell, especially amino acids.359,360 Acute hyponatremia is rarely

a cause of emergency department visits. In a total of 44,826 emergency department visits, only 2.9% were hyponatremic, and of those only 11 (0.8%) of the hyponatremic patients presented with acute neurologic symptoms. The cause of the symptomatic hyponatremia was variable, but included increased water intake either from polydipsia or the use of herbal teas for weight reduction, drug abuse with MDMA, and use of diuretic agents. Women appear more susceptible than men. Of the 11 patients in this series, nine were women.361 We have also encountered this problem in Shapiro’s syndrome, in which there is paroxysmal hypothermia and sometimes hyponatremia in association with agenesis of the corpus callosum.362

The entry of water into the brain is promoted by aquaporin, a water channel protein present in both brain and choroid plexus.363 In experimental animals, hyponatremia increases aquaporin-1 expression in the choroid plexus, allowing more water to enter the CSF and leading to apoptosis of cells surrounding the ventricular system.363 There is also increased immunoreactivity of aquaporin-4, a channel that allows entry of water into glia.364

Most patients with slowly developing or only moderately severe hyponatremia are confused or delirious (Table 5–19).

With more severe or more rapidly developing hyponatremia, asterixis and multifocal myoclonus often appear. Coma is a late and life-threatening phase of water intoxication, and both coma and convulsions are more common with acute than chronic hyponatremia. Neurologic symptoms are rare with serum sodium above 120 mg/L and convulsions or coma generally do not occur until the serum sodium values reach 95 to 110 mEq/L (again, the more rapidly the serum sodium falls, the more likely the symptoms are to occur at a higher level). Permanent brain damage may follow hypona-

Table 5–19 Clinical Manifestations

of Hyponatremic Encephalopathy

*Any manifestation may be observed at any stage, and some patients will have only minimal symptoms.

From Videen et al.,356 with permission.

tremic convulsions, and treatment with antiepileptic drugs is generally useless. The primary treatment must be directed at reversing the hyponatremia. Fraser and Arieff measured plasma sodium in 136 patients with hyponatremic encephalopathy. Premenopausal women developed severe symptoms at higher sodium levels than either postmenopausal women or men.357

Patient 5–21

A 33-year-old schoolteacher was admitted to the hospital in a coma. She had been working regularly until 2 days prior to admission when she

stayed home with nausea and vomiting. Two hours before admission she was noted to be dysarthric when speaking on the telephone. Later she was found by friends on the floor, unconscious and cyanotic. She had three generalized convulsions and was brought to the hospital. Her blood pressure was 130/180 mm Hg, her pulse 140 per minute, her respirations 24 per minute and regular, and her body temperature 38.78C. She did not respond to noxious stimulation. Her eyes deviated conjugately to the left at rest but turned conjugately to the right with passive head turning. Her pupils were 6 mm on the right and 5 mm on the left, and they briskly constricted to light stimulation. Both corneal reflexes were present. Her arms, hands, and fingers were flexed with spastic rigidity and irregular athetoid movements. Her legs and feet were rigidly extended. There were bilateral extensor plantar responses. She had three more convulsions that began in the right hand and then rapidly became generalized.

Despite extensive investigations and tests for metabolic aberrations or poisons, the only abnormalities found in this woman were of acute water intoxication. Her serum values were as follows: sodium 98 mEq/L, potassium 3.4 mEq/L, and osmolality 214 mOsm/L (normal ¼ 290 ± 5). The BUN was 10 mg/dL. Water restriction and infusion of 5% NaCl returned the electrolyte values to normal. After several days she opened her eyes, grimaced when pinched, and moved all extremities. Her muscles remained rigid, however, especially on the right side, and she continued to have bilateral extensor plantar responses. She had no further seizures. Six months later she remained severely demented and unable to care for herself.

Comment: The cause of this patient’s hyponatremia was never discovered. Excessive water intake in patients with no underlying metabolic problem, such as psychogenic polydipsia, is sometimes the cause. Hyponatremia has no pathognomonic signs or symptoms to suggest it in preference to other metabolic abnormalities, but should be suspected in patients who suddenly develop an unexplained encephalopathy or seizures, particularly if they are receiving diuretics, have carcinoma of the lung, or have neurologic disease. The diagnosis is possible if the serum sodium level falls below 120 mEq/L and highly likely when the sodium is below 115 mEq/L. The treatment of hyponatremia is to restore serum sodium to normal

levels. This is usually done using hypertonic saline.355,357,365 However, if the hyponatremia is

corrected rapidly (greater than 25 mEq/L in the first

24 to 48 hours), patients, particularly those with liver disease or other severe illnesses, are at risk for developing demyelinating lesions in the brain.357 Although called central pontine myelinolysis (see page 171), the disorder actually can affect the corpus callosum and other myelinated areas as well. Clinical symptoms include dysarthria, vertigo, quadriparesis, pseudobulbar palsy, confusion, and coma. The disorder can lead to death.339 Hence, rapid reversal of hyponatremia is generally limited to patients with severe and acute symptoms and is controlled at about 15 mEq/L/day, although there is no absolute cutoff below which central pontine myelinolysis does not occur.

Hyperosmolar States

Physicians sometimes induce transient hyperosmolality by therapeutically using hypertonic solutions containing sodium chloride or mannitol to treat cerebral edema. Complications of hyperosmolarity only occasionally arise during such efforts. Much more frequent are hyperosmolarity problems arising with hypernatremia or with severe hyperglycemia. Hypernatremia355 (Figure 5–9B) can be chronic or acute, the latter type being more prone to produce neurologic symptoms. Mild chronic hypernatremia occasionally occurs in chronic untreated diabetes insipidus caused by uncompensated water loss, but severe chronic hypernatremia with serum sodium levels in excess of 155 to 160 mEq/L is practically confined to the syndrome of essential hypernatremia. Essential hypernatremia usually is caused by a diencephalic abnormality and is characterized by a lack of thirst and a failure of ADH secretion to respond to osmoreceptor stimulation. In essential hypernatremia, serum sodium concentrations sometimes rise in excess of 170 mEq/L.366 We have seen this disorder mainly in patients with lesions of the preoptic area along the lamina terminalis, but patients have been reported without macroscopic lesions. Most patients with significant hypernatremia complain of fatigue and weakness. They usually become lethargic when sodium levels exceed 160 mEq/L; with elevations above 180 mEq/L, most become confused or stuporous and some die. A danger is that too rapid rehydration of such chronically hypernatremic subjects can produce symptoms