Laboratory Evaluations

The diagnosis of HE is based on the signs and symptoms of cerebral dysfunction in a setting of hepatic failure. Usually, standard laboratory test results, including serum bilirubin and hepatic enzymes, are abnormal. Products of normal hepatic function, including serum albumin and clotting factors, often are low, leading to elevation of the International Normalized Ratio (INR). Measurements of the arterial ammonia level may be helpful in diagnosing HE. When obtaining blood samples for an ammonia determination, care must be taken to be certain that the sample is of arterial origin (venous ammonia levels may be artificially high, especially after the outpouring of ammonia by muscle made ischemic by applying a tourniquet). The sample should be placed on ice and carried by hand to the laboratory for immediate analysis. Delays can result in ammonia production in the specimen, producing a spuriously elevated result.

Several consensus conferences sponsored by the International Society for Hepatic Encephalopathy and Nitrogen Metabolism have made recommendations concerning the use of electrophysiological and neuropsychological tests to evaluate patients with HE. The favored electrophysiological tests are those that are responsive to cortical function and include event-related electrical potentials (ERPs) such as P300 tests, the EEG, and visual and somatosensory ERPs. Neuropsychological tests are useful for diagnosing minimal HE. Domains to be evaluated, in descending order of desirability, include processing speed, working memory, anterograde verbal memory, visuospatial ability, anterograde visual memory, language, reaction time, and motor functions.

The EEG may be the most useful of the commonly used laboratory diagnostic tests. Bursts of moderate- to high-amplitude (100-300 µV), low-frequency (1.5-2.5 Hz) waves are the most characteristic abnormality. There are three stages in the EEG evolution: a theta stage with diffuse 4- to 7-Hz waves; a triphasic phase with surface-positive maximum deflections; and a delta stage characterized by random arrhythmic slowing with little bilateral synchrony. Computerized analysis of the EEG, designed to identify abnormalities in the spectra, may become a valuable means to identify patients with minimal encephalopathy. Abnormal ERPs may be found in patients with minimal encephalopathy. A combination of visual-evoked potentials, auditory P300s, and selected neuropsychological tests (such as Trailmaking Tests A and B) may be useful in detecting minimal encephalopathy in cirrhotic subjects. Although there has been less experience with auditory P300 potential recordings, in which the subject is asked to discriminate between a rare and common tone, differences in latencies and waveforms also have been associated with encephalopathy. It is uncertain whether this less complex approach to detecting minimal encephalopathy will prove to be more reliable and cost-effective than a focused neuropsychological test battery.

Neuropsychological tests are an underused and valuable means of diagnosing encephalopathy and monitoring the response to therapy (see Chapter 34). Sixty percent or more of all patients with cirrhosis with no overt evidence of encephalopathy exhibit significant abnormalities when given a battery of neuropsychological tests. Tests of attention, concentration, and visuospatial perception are the most likely to be abnormal. A test battery consisting of Trailmaking Tests A and B, serial dotting, line tracing, and the digit-symbol subtest of the Wechsler Adult Intelligence Scale, Revised, has been recommended for evaluating patients who may have hepatic encephalopathy. This battery is sensitive and relatively specific for the disorder, compared with other metabolic encephalopathies. Patients with alcoholic cirrhosis typically have more difficulty with memory deficits than patients with nonalcoholic cirrhosis. Even though these patients appear to be normal, the degree of impairment, particularly in the visuospatial sphere, may be severe enough to interfere with the safe operation of an automobile or other dangerous equipment. A study comparing patients with minimal encephalopathy with nonencephalopathic patients with cirrhosis and a third group with gastrointestinal disease, found that those with minimal encephalopathy performed the worst during an on-the-road driving test. Specific problems centered on handling, adaptation to road conditions, and accident avoidance. Language functions are usually normal. These data, combined with other studies showing that the quality of life is affected by these abnormalities, suggest that neuropsychological tests should be used more extensively for routine evaluation of all patients with cirrhosis, particularly those without overt evidence of HE.

Although the diagnosis of HE is typically made on the basis of clinical criteria, neuroimaging techniques are commonly employed to exclude structural lesions. Magnetic resonance imaging (MRI) and spectroscopic studies have revealed new insights into the pathophysiology of HE (Lockwood et al., 1997). On T1-weighted images, it is common to find abnormally high signals arising in the pallidum. These are seen as whiter-than-normal areas in this portion of the brain, as shown in Fig. 56.1. In addition to these more obvious abnormalities, a systematic analysis of MR images shows that the T1 signal abnormality is widespread and found in the limbic and extrapyramidal systems, and generally throughout the white matter. A generalized shortening of the T2 signal also occurs. This abnormality is less evident on visual inspection of the images because of the generally short duration of T2 signals. These abnormalities have been linked to an increase in the cerebral manganese content. The abnormalities become more prominent with time and regress after successful liver transplantation. The unexpected finding of high T1 signals in the pallidum should suggest the possibility of liver disease.

Fig. 56.1 T1-weighted magnetic resonance images from a patient with cirrhosis of the liver. Note high signal in basal ganglia, cerebral peduncles, and substantia nigra.

Proton MR spectroscopic techniques also have been applied to the study of patients with cirrhosis and are available in many centers. In the absence of absolute measures that are referable to concentrations, the signal of specific compounds is usually referenced to creatine and expressed as a compound-to-creatine ratio. There is general agreement among studies that an increase in the intensity of the signal occurs at approximately 2.5 ppm; this is attributed to glutamine plus glutamate. With high field–strength magnets, this peak can be resolved into its components, and the increase is attributed to glutamine, as expected on the basis of animal investigations. Correlations between the glutamine concentration, generally considered to be a reflection of exposure of the brain to ammonia and the severity of the encephalopathy, have led some to propose that MR spectroscopy may be useful in the diagnosis of HE.

Myoinositol and choline signals decrease, whereas N-acetylaspartate resonances (a neuronal marker) are consistently normal. Neuroimaging studies are not generally required in patients with HE. Imaging is useful in the diagnosis of coexisting structural lesions of the brain, such as subdural hematomas or other evidence of cerebral trauma, or complications of alcohol abuse or thiamine deficiency, or both, such as midline cerebellar atrophy, third ventricle dilatation, mamillary body atrophy, or high signal–strength lesions in the periventricular area on T2 FLAIR images.

Pathophysiology

The pathophysiological basis for the development of HE is still not completely known. However, treatment strategies for the disorder are all founded on theoretical pathophysiological mechanisms. A number of hypotheses have been advanced to explain the development of the disorder. Suspected factors include hyperammonemia, altered amino acids and neurotransmitters—especially those related to the γ-aminobutyric acid (GABA)-benzodiazepine complex—mercaptans, and short-chain fatty acids. Although none of the current hypotheses is completely capable of explaining the development of HE, it is likely that ammonia plays a central role. Because of the complexity of the metabolic derangements that attend liver disease, other factors may contribute synergistically to the development of this complex disorder.

Cerebral Blood Flow and Glucose Metabolism

Whole-brain measurements of cerebral blood flow (CBF) and metabolism are normal in patients with grade 0 to 1 HE. Reductions occur in more severely affected patients. Sophisticated statistical techniques designed to analyze images have made it possible to identify specific brain regions in which glucose metabolism is abnormal in patients with low-grade encephalopathy and abnormal neuropsychological test scores (Lockwood et al., 2002). These positron emission tomography (PET) data show clearly that minimal forms of HE are caused by the selective impairment of specific neural systems rather than global cerebral dysfunction. Reductions occur in the cingulate gyrus, an important element in the attentional system of the brain, and in frontal and parietal association cortices. These PET data are in accord with cortical localizations based on the results of neuropsychological tests. Fig. 56.2 shows the results of correlation analyses between scores on selected neuropsychological tests and sites of reduced cerebral glucose metabolism.

Fig. 56.2 Correlations between performance, as measured by age-corrected z scores, and metabolism for various subtests in the composite battery. Only those subjects able to complete the test are included in the analyses. The statistical parametric mapping Z image projections are as in the other figures. They all show significant correlations with bilateral parietal associative cortex, with increasing correlations with frontal regions.

(Used with permission from Lockwood, A.H., Weissenborn, K., Bokemeyer, M., et al., 2002. Correlations between cerebral glucose metabolism and neuropsychological test performance in nonalcoholic cirrhotics. Metab Brain Dis 17, 29-40.)

Role of Ammonia

Hepatic encephalopathy is linked to hyperammonemia. Patients with encephalopathy have elevated blood ammonia levels that correlate to a degree with the severity of the encephalopathy. Metabolic products formed from ammonia—most notably glutamine and its transamination product, α-ketoglutaramic acid—also are present in excess cerebrospinal fluid (CSF) in patients with liver disease. Treatment strategies that lower blood ammonia levels are the cornerstone of therapy.

Tracer studies performed with ¹³N-ammonia have helped clarify the role of this toxin in the pathophysiology of HE. Ammonia and other toxins are formed in the GI tract and carried to the liver by the hepatic portal vein, where detoxification reactions take place. Portal systemic shunts cause ammonia to bypass the liver and enter the system circulation, where it is transported to the various organs as determined by their blood flow. The liver is the most important organ for the detoxification of ammonia. However, in patients with portacaval shunting of blood, because of the formation of varices, TIPS, or other surgically created shunts, skeletal muscle becomes more important as the fraction of blood bypassing the liver increases. Under the most extreme conditions, muscle becomes the most important organ for ammonia detoxification. It is partly for this reason that nutritional therapy for patients should be designed to prevent development of a catabolic state and muscle wasting.

Ammonia is always extracted by the brain as arterial blood passes through the cerebral capillaries. When ammonia enters the brain, metabolic trapping reactions convert free ammonia into metabolites (Fig. 56.3). The adenosine triphosphate (ATP)-catalyzed glutamine synthetase reaction is the most important of these reactions. The blood-brain barrier is approximately 200 times more permeable to uncharged ammonia gas (NH³) than it is to the ammonium ion (NH⁴⁺); however, because the ionic form is much more abundant than the gas at physiological pH values, substantial amounts of both species appear to cross the blood-brain barrier. Because of this permeability difference and because ammonia is a weak base, relatively small changes in the pH of blood relative to the brain have a significant effect on brain ammonia extraction. As blood becomes more alkalotic, more ammonia is present as the gas and cerebral ammonia extraction increases; however, the role this has in the production of HE is not known. The permeability surface-area (PS) product of the blood-brain barrier may be affected by prolonged liver disease. However, the experimental data about this change are in conflict: one study reported an increase in the PS product, and another reported no change. An increased PS product could explain in part the toxin hypersensitivity that develops with time.

Fig. 56.3 Human ammonia metabolism. The brain becomes more sensitive to ammonia as time progresses. Although the reasons for this are largely unknown, studies of cerebral ammonia metabolism have shown that the blood-brain barrier is more permeable to ammonia in patients with liver disease than in controls. Thus at a given arterial ammonia concentration, more ammonia enters the brain of a patient with cirrhosis than a patient without cirrhosis. This observation may explain the presence of encephalopathy in patients with near-normal arterial ammonia levels. In addition, ammonia may cause anorexia by stimulating hypothalamic centers, leading to reductions in muscle mass and an impaired ability of muscle to detoxify ammonia. GI, Gastrointestinal.

(Adapted from Lockwood, A.H., McDonald, J.M., Reiman, R.E., et al., 1979. The dynamics of ammonia metabolism in man: effects of liver disease and hyperammonemia. J Clin Invest 63, 449-460.)

Other Pathophysiological Mechanisms

Neuropathology

The Alzheimer type II astrocyte is the neuropathological hallmark of hepatic coma. An account of the original descriptions of this change was provided in translation by Adams and Foley in 1953. In this report, they presented their own findings of this astrocyte change in the cerebral cortex and the lenticular, lateral thalamic, dentate, and red nuclei, offering the tentative proposal that the severity of these changes might be correlated with the length of coma. The cause of the astrocyte change was established by studies that reproduced the clinical and pathological characteristics of HE in primates by continuous infusions of ammonia. In studies of rats with portacaval shunts, astrocyte changes become evident after the fifth week. Before coma develops, astrocytic protoplasm increases and endoplasmic reticulum and mitochondria proliferate, suggesting that these are metabolically activated cells. After the production of coma, the more typical signs of the Alzheimer type II change became evident as mitochondrial and nuclear degeneration appeared. Norenberg (2007) suggested that HE is an astrocytic disease, although oligodendroglial cells are affected as well. More recent evidence from his laboratory has shown that ammonia affects a wide variety of astrocytic functions and aquaporin-4.

The neuropathological-neurochemical link between astrocytes and the production of hyperammonemic coma is strengthened by immunohistochemical studies that localized glutamine synthetase to astrocytes and their end-feet. Similar findings for glutamate dehydrogenase have been described. Long-standing or recurrent HE may lead to the degenerative changes in the brain characteristic of non-Wilson hepatocerebral degeneration. Brains of these patients have polymicrocavitary degenerative changes in layers five and six of the cortex underlying white matter, basal ganglia, and cerebellum. Intranuclear inclusions that test positive by periodic acid-Schiff also are seen, as are abnormalities in tracts of the spinal cord.

Treatment

Ideally, the management of cirrhosis should involve a cooperative effort between hepatologists, surgeons, neurologists, and psychologists, with additional input from nurses and dieticians. Practice guidelines published by the American College of Gastroenterology identify four goals: (1) provide supportive care, (2) identify and treat precipitating factors, (3) reduce the nitrogenous load from the gut, and (4) assess need for long-term therapy (Blei and Cordoba, 2001; Ferenci et al., 2002).

Initial diagnostic and therapeutic efforts should be directed at the identification and mitigation of precipitating factors and reducing the nitrogenous load arising from the GI tract. This is accomplished by a brief withdrawal of protein from the diet and the administration of cleansing enemas, followed by the use of lactulose. Antibiotics may be used as an alternative to lactulose. After the acute phase of HE, patients should receive the maximum amount of protein that is tolerated. Prolonged periods of protein restriction should be avoided. Protein is required for the regeneration of hepatocytes and prevention of a catabolic state and muscle wasting.

In patients who have cirrhosis without overt encephalopathy, diagnostic efforts should be directed toward identifying patients with minimal encephalopathy and monitoring the effects of treatment. The inappropriate terms, subclinical or latent HE have been too commonly applied to patients with minimal encephalopathy. Patients with minimal encephalopathy have a diminished quality of life and benefit from therapy, typically lactulose. Although rigorous criteria have not been developed to establish this diagnosis, deficits on neuropsychological test scores are usually used as the criterion. Some have advocated the use of computerized EEG analysis for this purpose, with a focus on abnormal slowing seen on an analysis of the spectrum. Follow-up testing is needed to monitor treatment.

Complications and Prognosis

Although studies done over 2 decades ago demonstrated that patients with hepatic coma were more likely to survive with minimal residua, this disorder still carries a substantial risk of death. Transplant-free survival at 1 year is less than 50% after an initial episode and less than 25% at 3 years. To aid in the selection of patients for transplantation, a simple rating system or MELD (Model for End-stage Liver Disease) score has been developed and validated to predict mortality. The MELD score is based on the bilirubin, serum creatinine, and the international normalized ratio (INR). The higher the MELD score, the worse the prognosis. An on-line MELD calculator and a pediatric equivalent can be found at the United Network for Organ Sharing web site (www.unos.org/resources/MeldPeldCalculator.asp?index=98).

The incidence of HE is probably underestimated, mainly because neurologists are not usually the primary physicians of these patients, and early subtle signs of cerebral dysfunction may be missed. It is important to establish the diagnosis of HE promptly and proceed with vigorous treatment. Although HE is potentially completely reversible, prolonged or repeated episodes risk transforming this reversible condition into non-Wilson hepatocerebral degeneration, a severe disease with fixed or progressive neurological deficits including dementia, dysarthria, gait ataxia with intention tremor, and choreoathetosis. Other patients may develop evidence of spinal cord damage, usually manifested by a spastic paraplegia. This complication may be a part of the spectrum of hepatocerebral degeneration. Differentiating correctly between early myelopathy or hepatocerebral degeneration and the motor abnormalities that characterize reversible encephalopathy may not always be possible. Because of the high sensitivity of MRI, it is possible that this technology will aid in this difficult task. Patients with HE may develop toxin hypersensitivity, wherein previously innocuous levels of toxins cause symptoms. This concept implies that there may be a steadily increasing risk for developing permanent neurological damage as toxin hypersensitivity evolves.

Pathophysiology

Clinically, patients with uremic encephalopathy exhibit many of the signs and symptoms described earlier in this chapter. Perhaps the most notable difference between these patients and those with other forms of metabolic encephalopathy is the frequent coexistence of signs of obtundation (suggesting nervous system depression) and twitching, myoclonus, agitation, and occasionally seizures (suggesting neural excitation). Little is known of the pathophysiology of uremic encephalopathy. As in HE, the complexity of the normal kidney’s functions makes it likely that failure of the organ leads to a variety of abnormalities that exert synergistic deleterious effects on the brain. As in other metabolic encephalopathies and other conditions associated with a depression of consciousness, CBF and metabolism are reduced.

Water, Electrolyte, and Acid-Base Balance

Although derangements in electrolyte, water, and acid-base balance are common in patients with renal failure, they usually do not make a substantial contribution to the development of uremic encephalopathy. Disordered water balance is, however, a major factor in the syndrome of dialysis disequilibrium. Many patients complain of headache, fatigue, and other relatively nonspecific symptoms at the time of dialysis that are attributable to the removal of free water and solutes from the vascular compartment and a lag in reestablishing a new steady-state osmotic equilibrium with the brain. More severe forms of dialysis disequilibrium are now rare. Before the current level of sophistication in equipment, membranes, and schedules for dialysis was developed, severe abnormalities of the EEG, epileptic seizures, coma, and even death occurred as the result of this syndrome.

Calcium and Parathyroid Hormone

Abnormal calcium metabolism and abnormal control of the parathyroid glands are common in uremic patients, including those receiving dialysis. Experimental studies have shown a doubling of the brain calcium content and serum parathyroid hormone levels within days of the onset of acute renal failure. EEG slowing correlates with elevations in the plasma content of the N-terminal fragment of parathyroid hormone. Treatment with 1,25-dihydroxyvitamin D leads to improvements in the EEG and reductions in N-terminal fragment parathyroid hormone concentrations. Brain calcium concentrations may be related to the activity of an ATP-dependent sodium-calcium transporter protein.

Neurotransmitters

Disorders of plasma amino acids, most notably glutamine, glycine, aromatic and branched-chain amino acids, and potential relationships to GABA, dopamine, and serotonin, have led to speculations that neurotransmitter function may be abnormal in patients with uremic encephalopathy. Others have suggested that brain calcium abnormalities may exert an effect on neurotransmitter release. These hypotheses remain unproven.

Treatment and Its Complications

Dialysis is the primary treatment for uremic encephalopathy. This may be preceded by a period of peritoneal dialysis, which can be administered to ambulatory patients. Many patients ultimately require transplantation.

Epileptic seizures, including nonconvulsive seizures, occur in up to one-third of all uremic patients. In evaluating patients with seizures, it is essential to determine whether the seizure is the result of uremia or the consequence of some other coexisting or causative illness such as malignant hypertension with encephalopathy, intercurrent infection, dialysis disequilibrium syndrome, or cerebral infarction. Usually the seizures caused by uncomplicated uremia are generalized, but focal motor seizures and epilepsia partialis continua occur.

The treatment of uremic seizures is complicated by abnormalities of anticonvulsant metabolism and plasma binding encountered in patients with renal failure; phenytoin, a mainstay in seizure treatment, is particularly affected. Regardless of the route of phenytoin administration, drug levels in uremic patients are lower than in normal controls, and plasma levels of the metabolite 5-phenyl-5-para-hydroxylphenylhydantoin are higher. The half-life of phenytoin is shortened in uremia and unrelated to the binding of phenytoin to plasma proteins or to the volume of distribution. Plasma protein-binding studies of phenytoin in normal and uremic patients show that normal people have approximately 8% unbound (or free) plasma protein, whereas uremic patients have between 8% and 25% in the unbound state. The unbound fraction correlates well with both the blood urea nitrogen and the creatinine concentration in blood, with better correlation with creatinine than blood urea nitrogen. It is critical to use the free phenytoin drug level rather than the more commonly used total drug level when adjusting the phenytoin dose. As a general rule, the free level should be kept between 1 and 2 µg/mL, roughly 10% of the therapeutic level for total phenytoin. Phenytoin toxicity is difficult to manage in uremic patients because the drug is not removed by dialysis.

Phenobarbital is also a useful drug for treating seizures in uremic patients in spite of the fact that it is excreted by the kidneys. Plasma phenobarbital levels are unaffected by uremia and may be used to monitor therapy.

Treating renal failure by dialysis and transplantation has given rise to a number of neurological syndromes. Because of the large number of patients being treated by these modalities, especially dialysis, it is important to recognize currently described complications and to be alert to the possibility that new syndromes will emerge as treatment modalities evolve. Although dialysis is clearly an important life-sustaining treatment for patients with renal failure, two important neurological syndromes related to this modality are recognized: dialysis disequilibrium syndrome and dialysis dementia syndrome. The former is an acute syndrome that may be seen during or after a single dialysis treatment; the latter is a chronic condition that emerges subacutely or chronically after prolonged treatment by dialysis. The treatment and prophylaxis of these syndromes have become much more successful as our understanding of their pathophysiology has improved. Dialysis disequilibrium syndrome occurs during or immediately after treatment by either hemodialysis or peritoneal dialysis. Symptoms may be subtle and include delirium, seizures (usually grand mal, although focal seizures may occur), coma, and death. Other symptoms that may be encountered include disorientation, headache (often associated with nausea, restlessness, or fatigue), muscle cramps, and tremulousness. During the acute syndrome, disorganization and slowing of the EEG may be seen, and CSF pressure may be elevated. EEGs recorded during chronic maintenance hemodialysis show that there is usually some abnormality during the treatment of stable patients, with the most significant abnormalities seen in patients reporting symptoms.

The symptoms of dialysis disequilibrium are probably caused by brain swelling and the ensuing traction on pain-sensitive intracranial structures. Uremic patients have increased serum and brain osmolality due to accumulation of urea and idiogenic osmoles. When rapid hemodialysis was compared to slow hemodialysis, the water and osmole content of brains of the animals treated by rapid dialysis was greater than in those treated by slow dialysis. Urea concentration in the CSF and brain exceeds the plasma urea concentration in both treatments. Rapid hemodialysis also is associated with the development of CSF acidosis and a significant osmotic gradient between blood and brain not explained by sodium, potassium, chloride, or urea concentration. These conditions result in the obligatory water retention by the brain relative to blood, which causes the brain to swell. Idiogenic osmoles are probably of critical importance in the development of this syndrome. Presumably, under conditions of slower dialysis, the brain has an opportunity to rid itself of idiogenic osmoles and is less susceptible to the development of edema during dialysis. The presence of acidosis in the central nervous system also may be important. Recognizing these mechanisms has led to a reduction in the severity and incidence of this debilitating disorder.

The dialysis dementia syndrome is a more serious but rare condition. It is a subacute syndrome of impaired memory with personality changes, apractic dysarthric speech, myoclonus, seizures (usually multifocal), and an abnormal EEG characterized by slowing with multifocal bursts of more profound slowing and spikes. Aluminum levels in the brains of patients with the syndrome are higher than the levels in controls, in uremic patients not receiving dialysis, and in uremic patients on dialysis but without the syndrome. Epidemiological studies of the relationship of the syndrome to the aluminum content of dialysate fluid have established the latter as the probable source of the aluminum and the most likely cause of the syndrome. Although it seems clear that the majority of cases of dialysis dementia can be related to aluminum in the dialysate, unexplained sporadic cases occur in some patients with low aluminum levels. In these patients, blood aluminum levels appear to be high, suggesting that GI aluminum absorption may be of occasional importance in the pathogenesis of the disorder. Treatment of the syndrome has been difficult, and little success has been reported.

Physiology

Clinical Aspects of Hypoglycemia

Diagnosing hypoglycemia on the basis of clinical symptoms is fraught with hazards. Although the majority of symptoms are attributable to nervous system dysfunction, they are extremely varied, nonspecific, and not always present even when blood glucose levels are very low. Because of the close link between the symptoms of hypoglycemia and the brain, some authors use the term neuroglycopenia to refer to symptomatic hypoglycemia. There are three syndromes: acute, subacute, and chronic.

The acute syndrome most commonly develops as the result of the action of short-acting insulin preparations or oral antihyperglycemics and begins with vague symptoms of malaise, feeling detached from the environment, restlessness associated with hunger, nervousness that may lead to panic, sweating, and ataxia. Patients may recognize these symptoms. The symptoms respond quickly to oral or parenteral glucose. An EEG performed during this period may reveal nonspecific abnormalities. Attacks may end spontaneously or proceed rapidly to generalized seizures and coma, with the attendant risk of permanent brain injury. These patients may arrive in the emergency department in a coma with no history.

The subacute syndrome is the most common form and occurs in the fasting state. Most of the symptoms listed for the acute syndrome are absent. In their place is a slowing of thought processes and a gradual blunting of consciousness with a retention of awareness, although amnesia for the episode is common. The diagnosis may be difficult to establish until the possibility of hypoglycemia is considered or routine testing uncovers the abnormality. Hypothermia is encountered frequently in this form of the disorder, and unexplained low body temperatures always should be followed by a blood glucose measurement.

Chronic hypoglycemia is rare and, if confirmed, suggests a probable insulin-secreting tumor or obsessively good control by a diabetic. Plasma hemoglobin A_1c levels are helpful in making this differential diagnosis. This syndrome is characterized by insidious changes in personality, memory, and behavior that may be misconstrued as dementia. Unlike those of the acute and subacute forms of hypoglycemia, these symptoms are not relieved by administering glucose, suggesting the presence of neuronal injury. Clinical improvement after removal of the source of the exogenous insulin is gradual, extending over periods as long as a year.

The symptoms of sweating, tremor, and the sensation of warmth may be attributed to activity of the autonomic nervous system. The inability to concentrate, weakness, and drowsiness are attributable to neuroglycopenia. Hunger, blurred vision, and other symptoms are of uncertain cause.

Diabetics may develop hypoglycemia without being aware of the usual warning symptoms, a condition known as hypoglycemia unawareness, which may occur in a complete or partial form in up to 17% of all episodes in patients with type 1 diabetes. The underlying mechanisms appear to be related to the occurrence of prior episodes of hypoglycemia, altered neuroendocrine responses that regulate blood glucose levels, and central nervous system dysfunction that may interfere with symptom detection and analysis. This is supported by studies that show that patients with the syndrome exhibit a reduction in β-adrenergic sensitivity. In these patients, the glucose concentration needed to initiate counterregulatory hormonal response were lower than normal. Imaging studies using FDG and PET to measure neuronal activity in the subthalamic area, a site implicated as a glucose sensor, showed an abnormal response in patients with symptoms of hypoglycemia unawareness.

The presence of the unawareness syndrome poses a special challenge for these patients, their caregivers, and colleagues. Precautions should be taken to minimize the chance that a patient with the syndrome might have a prolonged and unrecognized period of hypoglycemia that could result in permanent injury to the brain; the patient should not be allowed to drive, make critical decisions, and the like while in an impaired state.

Some special problems are associated with detecting hypoglycemia in neonates and children, centering on the various nonspecific symptoms (e.g., pallor, irritability, and feeding difficulties) and on the variable sensitivities of individual children to a given plasma glucose concentration. As with adults, the diagnosis is most likely to be made when the physician consciously keeps his or her index of suspicion high and when glucose measurements are done routinely when there is any doubt about a diagnosis. The risk of missing the diagnosis and having irreversible neuronal injury develop in the patient justifies liberal use of screening measures and, in some cases, presumptive treatment with parenteral glucose. The increasing use of home glucose test devices should help minimize risks to these patients.

Because of the complexity of glucose homeostasis, the causes of hypoglycemia are many and varied, and a detailed discussion is beyond the scope of this chapter. In general, most authors present a physiological classification as shown in Box 56.1.

Drugs are an important cause of hypoglycemia. In some cases, the effect of a drug may be potentiated by a restriction of food intake. Age-varying causes have been found and should aid in the diagnosis of the disorder. In the newborn period, maternal administration of sulfonylureas and other possible hypoglycemic agents that appear in breast milk dominate as a cause of hypoglycemia. From newborn to 2 years of age, salicylate ingestion dominates. Surprisingly, alcohol predominated as a cause in the 2- to 7-year age group. Alcohol-containing cough syrups and alcoholic beverages were responsible. Sulfonylureas and oral hypoglycemics again dominate in the 11- to 30-year and 50-and-older age groups. Alcohol predominated between the ages of 30 and 50 years. Significant numbers of patients in most age groups were encountered in whom beta-blockade with propranolol was a factor in masking the symptoms of developing hypoglycemia. The use of beta-blockers in patients receiving insulin or oral hypoglycemic agents therefore should be avoided. A number of risk factors have been recognized that predispose to the development of hypoglycemia. These include (in addition to diabetes) decreased caloric intake (usually related to severity of some illness or disruption of dietary routines), uremia, liver disease, infection, shock, pregnancy, neoplasia, and burns.

Hypoglycemia is associated with a substantial morbidity. A study of 600 patients with diabetes showed that the frequency of severe hypoglycemia was 1.60 episodes per patient per year and that it occurred twice as often in patients with the type 1 form of the disorder. Among patients with severe episodes of hypoglycemia, injuries and convulsions occurred at rates of 0.04 and 0.02 episodes per patient per year, respectively. Five patients had automobile accidents caused by hypoglycemia. Patients with episodes of severe hypoglycemia were more likely to have had prior severe episodes, were on insulin longer, and had lower hemoglobin A_1c concentrations. A southern California medical examiner found 123 deaths caused by hypoglycemia in a series of 54,850 autopsies. The risk of death is highest in patients with the most severe hypoglycemia and the largest number of risk factors. Among hospitalized patients, whites have the lowest mortality rate (approximately 6%), whereas black and Hispanic patients have mortality rates of 30% and 46%, respectively. Hypoglycemia is a medical emergency, and this diagnosis should be considered among virtually all patients with an altered mental status of unknown cause. Most of these patients should be treated with parenteral glucose after adequate blood samples are obtained for laboratory testing. It is prudent to draw extra blood so that insulin and hemoglobin A_1c levels can be measured if indicated by the patient’s subsequent course. These measures are particularly important in patients with obscure histories and in whom factitious hypoglycemia may be present. The total amount of glucose administered may be of little consequence if the patient is found to have a normal or elevated plasma glucose concentration. Exogenous glucose is harmful to the brain during hypoxia or ischemia, and caution must be exercised in administering glucose to this group of patients.

Clinical Aspects of Hyperglycemia

Although there are many causes of hyperglycemia, diabetic ketoacidosis (DKA), nonketotic hyperosmolar coma, and iatrogenic factors such as parenteral hyperalimentation are the most important. DKA is a relatively common disorder, predominantly affecting patients with type 1 diabetes. It is frequently precipitated by an infectious process in a patient who has been otherwise stable, develops over several days, and is heralded by polyuria and polydipsia caused by the osmotic diuresis produced by glucosuria. These symptoms are followed by anorexia, nausea, disorientation, and coma. On physical examination, sustained hyperventilation is common, especially in patients with severe acidosis. The diagnosis is frequently suspected on the basis of clinical findings, but laboratory data including the plasma glucose, arterial blood gases, electrolytes, and an appropriate test for ketone bodies are essential for confirming the diagnosis and management.

Nonketotic hyperosmolar coma, by contrast, is a feature of type 2 diabetes and is thus encountered in older patients, commonly as the first manifestation of the disease. This syndrome evolves more slowly than DKA, and the period of polyuria is more prolonged, leading to much more severe dehydration. Because glucose is a less effective dipsogen than other solutes, water-seeking behavior is not as strong in this group of patients as it is in patients with hypernatremic hyperosmolality, thus promoting the development of dehydration. Suppressed water-seeking behavior combined with the inhibitory effect of hypertonicity on insulin release can lead to severe dehydration and hyperglycemia that can be in excess of 2000 mg/dL. The disorder’s signs and symptoms are those of hyperosmolality, hypovolemia, and cerebral dysfunction, with epileptic seizures occurring in some individuals. Precipitating factors include infection, gastroenteritis, pancreatitis, and occasionally, treatment with glucocorticoids or phenytoin. Because many total parenteral nutrition protocols use solutions with high glucose contents, hyperglycemia is a potential complication of their use.

DKA is an insulin-deficient state, and insulin is the cornerstone of therapy. In the absence of insulin, peripheral glucose uptake and glycogen formation are reduced, and glycogenolysis and lipolysis are accelerated, leading to the formation of acidic ketone bodies and hyperglycemia. When plasma glucose levels exceed the renal threshold (usually approximately 180 mg/dL), glucosuria and a forced osmotic diuresis ensue. The treatment of DKA is designed to reverse these pathophysiological abnormalities and consists of administering insulin to enhance glucose uptake, enhance glycogen formation by noncerebral tissues, and reduce the rate of ketone body formation occurring during low-insulin, high-glucagon states that promotes the entry of fatty acids into mitochondria, where they are converted to ketones. Replacing fluid and electrolytes also is required, as is treatment of precipitating factors. It is important to remember that overly vigorous treatment with rapid restoration of plasma osmolality to normal levels can lead to the development of cerebral edema (see Complications of Treatment).

Neurologists may become involved in the diagnosis and management of nonketotic hyperosmolar coma when a patient has no prior history of diabetes and is brought to the emergency department with unexplained coma or seizures. Because hyperosmolality and the associated hypovolemia are usually much more severe in this condition than in DKA, maintaining an adequate blood pressure and cardiac output are the first priorities in treatment. One or two liters of normal saline should be given rapidly to restore blood volume and to begin to reduce plasma osmolality. Additional fluid and insulin therapy then can be initiated as indicated by laboratory and clinical data. These patients may require intensive monitoring with arterial and catheters to monitor the circulatory system status and avoid inducing a volume overload; at the same time, adequate amounts of fluid should be given to restore osmolality to normal levels. The exact mechanisms leading to the development of the syndrome, particularly the absence of ketosis, are not fully explained.

Complications of Treatment

Although treatment of DKA has improved, the mortality rate is still appreciable. The majority of patients who succumb do so because of cardiovascular collapse or from complications of the precipitating factor. A small number of patients die unexpectedly when laboratory and clinical indicators all show initial improvement.

Clinically, patients with DKA who die experience rapid neurological then cardiovascular deterioration. Postmortem examinations of the brain shows lesions similar to those seen in acute asphyxia, including capillary dilation with perivascular and pericellular edema. Death is heralded by a rapid evolution of signs and symptoms indicating an increase in ICP. About half of patients die during the initial episode of DKA. The rate and degree to which the plasma glucose level is lowered is not a major risk factor for death.

Some degree of cerebral edema attends the treatment of most patients with DKA, occasionally to the high level of 600 mm H₂O CSF pressure, as shown in Fig. 56.4.

Fig. 56.4 Blood glucose and intracranial pressure during treatment of diabetic ketoacidosis. The untreated hyperosmolar state leads to the intracerebral accumulation of idiogenic osmoles. As blood glucose and osmolality levels decrease during treatment, free water enters the brain more rapidly than idiogenic osmoles are shed, leading to an increase in intracranial pressure from the swollen brain. This mechanism presumably operates in all cases in which hyperosmolality is corrected rapidly. CSF, Cerebrospinal fluid.

(Reprinted with permission from Clements, R.S. Jr., Blumenthal, S.A., Morrison, A.D., et al., 1971. Increased cerebrospinal fluid pressure during treatment of diabetic ketoses. Lancet 2, 671-675.)

The data suggest that at least mild clinically silent cerebral swelling may be much more common than is realized in cases of DKA. Rare unknown factors appear to trigger a malignant increase in intracranial pressure in a small number of patients, producing a syndrome characterized by rapid neurological deterioration and death caused by neurological and circulatory collapse. Published experience suggests that if this diagnosis is made, prompt aggressive treatment of cerebral edema is indicated, preferably using ICP monitoring as a guide to therapy. Nevertheless, the associated mortality rate is high.

Glucose and Cardiopulmonary Resuscitation

A number of studies suggest that hyperglycemia is associated with an increase in the severity of complications of cerebral ischemia and hypoxia. The presumption is that blood, and hence brain, glucose levels are higher in hyperglycemic individuals, and that this glucose produces more lactate during the hypoxic-ischemic insult. This sequence is shown in Fig. 56.5, in which the metabolic consequences of decapitation in animals are shown. Glucose is metabolized anaerobically to lactate, which with the hydrolysis of ATP causes acidosis. A large number of experimental studies suggest that cerebral acidosis is an important determinant of brain injury, including acidosis associated with lactate production during ischemia. The results of these studies have been extended to humans, in whom a less favorable outcome was suggested for stroke patients with diabetes and hyperglycemia compared with euglycemic diabetic stroke patients.

Fig. 56.5 Neurochemical consequences of decapitation. Experimental animals were decapitated and then frozen at various times thereafter. Brains were assayed for metabolites, as shown in the figure. As can be seen, high-energy phosphates are depleted rapidly. Glucose and glycogen also are consumed, generating lactate as metabolism changes from the normal aerobic condition to an anaerobic state. The changes shown in this figure are analogous to those following acute hypoxia or cerebral infarction. ATP, Adenosine triphosphate; P-creat, phosphocreatine.

(Data from Lowry, O.H., Pasonneau, J.V., 1964. The relationships between substrates and enzymes of glycolysis in brain. J Biol Chem 239, 31-42.)

A number of animal studies have shown that the risk of neurological injury during resuscitation from cardiopulmonary arrest increases if exogenous glucose is administered. This issue has been investigated in humans. Investigators randomly administered 5% dextrose in water or half-normal saline while treating out-of-hospital cardiopulmonary arrest. These treatments did not produce significant differences among three measures of outcome: awakening, survival to admission to the hospital, or discharge from the hospital. However, because patients with ventricular fibrillation or asystole with high blood glucose levels at the time of admission to the hospital were less likely to awaken than patients with lower blood glucose levels, they concluded that it is appropriate to restrict the amount of glucose administered during cardiopulmonary resuscitation unless hypoglycemia is present.

Disordered Osmolality

Osmotic Homeostasis

The serum, and hence whole-body osmolality, are regulated by complex neuroendocrine and renal interactions that control thirst and water and electrolyte balance. When serum osmolality increases, the brain loses volume; when osmolality falls, the brain swells. Events related to water loss are illustrated in Fig. 56.6. The brain has little protection in terms of volume changes when osmotic stress is acute. Examples of acute osmotic stress may be found in patients with heat stroke, inadvertent solute ingestion (particularly in infants), massive ingestion of water (which may be psychogenic), hemodialysis, and diabetics with nonketotic coma. Recent reports also suggest that excessive water consumption occurs in some marathon runners, leading to acute water intoxication. When osmotic stress is applied more slowly over a longer period, the predicted volume changes are smaller than would be expected. The mechanisms that underlie these protective adaptations are not known completely but involve the gain of amino acids in the case of the hyperosmolar state and the loss of potassium in the hypo-osmolar state. Experimental studies have failed to identify all of the osmotically active particles that must exist in the brain after a given osmotic stress is applied. These unidentified molecules are called idiogenic osmoles.

Fig. 56.6 Water balance and the brain. A reduction in water (or an increase in water loss or solute gain) stimulates thirst and vasopressin release, leading to increased water conservation and intake, which in turn reduces vasopressin levels and ends thirst. Excessive water intake or excessive water loss leads to hypo-osmolality or hyperosmolality and the loss or gain of osmotically active particles in the brain, respectively. Excessively rapid treatment of these conditions may lead to the development of neurological symptoms. ADH, Antidiuretic hormone.

Clinical Features

The signs and symptoms of deranged osmolality depend on the severity of the disturbance and the length of time elapsed between onset and clinical presentation. Often these syndromes are of insidious onset. Typical complaints are nonspecific and include malaise, nausea, and lethargy, leading to obtundation and coma. Headache, due to brain swelling, and epileptic seizures may be encountered in patients with hyponatremia.

Disorders of Calcium Metabolism

Hypercalcemia and hypocalcemia both have diverse causes associated with disordered parathyroid gland function and a variety of other conditions. Under normal circumstances, approximately half of the total serum calcium is bound to proteins, mainly albumin, and half is in the ionized form, the only form in which it is active. When there is doubt about the Ca²⁺ concentration, as in patients with hypoalbuminemia, direct measurement of Ca²⁺ with ion-sensitive electrodes may be required.

Hypercalcemia is associated with hyperparathyroidism, granulomatous diseases (especially sarcoidosis), treatment with drugs including thiazide diuretics, vitamin D, calcium itself, tumors that have metastasized to bone, and thyroid disease. Many cases are idiopathic.

The symptoms and signs of hypercalcemia may be protean. Severe hypercalcemia affects the brain directly, causing coma in extreme cases. In this group of patients, metastatic tumors are common, especially multiple myeloma and tumors of the breast and lung. Cancer patients seem to be particularly vulnerable to developing hypercalcemia after a change in therapy. Less severe hypercalcemia may cause altered consciousness, with a pseudodementia syndrome and weakness. GI, renal, and cardiovascular abnormalities also may be present.

Severe hypercalcemia is life threatening. Initial treatment consists of a forced diuresis using saline and diuretics. Because the volumes of saline that are required may be large, a central venous or Swan-Ganz catheter may be needed to monitor therapy. Once the initial phase of treatment is accomplished, further management is determined by the cause of the hypercalcemia.

Hypocalcemia usually is associated with hypoparathyroidism. The neurological symptoms are attributable to the enhanced excitability of the nervous system. Symptoms include paresthesias around the mouth and fingers, cramps caused by tetanic muscle contraction, and in more extreme cases, epileptic seizures. In more chronic hypocalcemia, headache secondary to increased intracranial pressure may occur, and extrapyramidal signs and symptoms such as chorea or parkinsonism may be encountered. These patients may have calcification of the basal ganglia, evident on computed tomography of the brain. The physical examination should include attempts to elicit Chvostek and Trousseau signs. Cataracts and papilledema may be seen.

Severe hypocalcemia should be treated with infusions of calcium to treat or prevent epileptic seizures or laryngeal spasms, both of which are life-threatening but unusual complications. Chronic therapy usually involves administration of calcium and vitamin D. Care must be taken to avoid hypercalcemia and hypercalciuria. Consultation with an endocrinologist is prudent, but continued neurological care may be necessary, especially in patients with extrapyramidal syndromes, who may require specific treatment.

Disorders of Magnesium Metabolism

Hypermagnesemia is an unusual condition because of the ease with which normal kidneys act to preserve magnesium homeostasis. Hypermagnesemia is most commonly due to infusions given to treat blood pressure and nervous system dysfunction in patients with eclampsia. Care must be observed in administering magnesium to patients with renal failure. This group of patients is the most vulnerable and the most likely to develop hypermagnesemia because the kidneys’ homeostatic function is impaired. Hypocalcemia potentiates the effects of excess magnesium. Severe hypermagnesemia is life threatening, and concentrations in excess of 10 mEq/L must be treated. Discontinuation of magnesium preparations usually suffices. When cardiac arrhythmias are present or circulatory collapse is possible, calcium must be infused, especially when hypocalcemia is present.

Isolated hypomagnesemia is unusual. Magnesium deficiency usually occurs in patients with deficiencies of other electrolytes. Hypomagnesemia may result from a diet deficient in magnesium, including prolonged parenteral alimentation with insufficient or no magnesium replacement, malabsorption, and alcoholism. Excess magnesium loss from the GI tract or the kidneys may also lead to calcium deficiency. Magnesium deficiency is usually part of a complex electrolyte imbalance, and accurate diagnosis and management of all aspects of the state are necessary to ensure recovery.

Pure magnesium deficiency has been produced experimentally and is expressed primarily through secondary reductions in serum calcium levels in spite of adequate dietary calcium intake. Ultimately, anorexia, nausea, a positive Trousseau sign, weakness, lethargy, and tremor develop but are rapidly abolished by magnesium repletion. Balance studies indicate that magnesium deficiency causes a positive sodium and calcium balance and a negative potassium balance. Magnesium is necessary for proper mobilization and homeostasis of calcium and the intracellular retention of potassium. Some of the effects of magnesium depletion are secondary to abnormalities of potassium and calcium metabolism.

Disorders of Manganese Metabolism

Manganese poisoning occurs primarily in manganese ore miners and causes parkinsonism. As presented in the section on HE, there is increasing evidence that accumulation of this metal in the brain causes hyperintensities on T1-weighted MRI and may be associated with disorders of dopaminergic neurotransmission.