Neurology_Adams

Neurology_Adams. A severe and prolonged episode of hypoglycemia may result in permanent impairment of intellectual function as well as other neurologic residua, like those that follow severe anoxia. We also have observed states of protracted coma, as well as relatively pure Korsakoff amnesia. However, one should not be hasty in prognosis, for we have observed slow improvement to continue for 1 to 2 years. Recurrent hypoglycemia from an islet cell tumor may masquerade for some time as an episodic confusional psychosis or convulsive illness; diagnosis then awaits the demonstration of low blood glucose or hyperinsulinism in association with the neurologic symptoms. We saw a man in the emergency department whose main complaint was episodic inability to dial a touchtone telephone and a mild mental fogginess; he was found to have an insulinoma.


Neurology_Adams

Neurology_Adams. Functional or reactive hypoglycemia is the most ambiguous of all syndromes related to low blood glucose. This condition is usually idiopathic but may precede the onset of diabetes mellitus. The rise of insulin in response to a carbohydrate meal is delayed but then causes an excessive fall in blood glucose, to 30 to 40 mg/dL. The symptoms are malaise, fatigue, nervousness, headache and tremor, which may be difficult to distinguish from anxious depression. Not surprisingly, the term functional hypoglycemia has been much abused, being applied indiscriminately to a variety of complaints that would now be called chronic fatigue syndrome or an anxiety syndrome. In fact, a syndrome attributable to functional or reactive hypoglycemia is infrequent and its diagnosis requires the finding of an excessive reaction to insulin, low blood glucose during the symptomatic period, and a salutary response to oral glucose.


Neurology_Adams

Neurology_Adams. In all forms of hypoglycemic encephalopathy, the major damage is to the cerebral cortex. Cortical nerve cells degenerate and are replaced by microglia cells and astrocytes. The distribution of lesions is similar, although probably not identical to that in hypoxic encephalopathy. The cerebellar cortex is less vulnerable to hypoglycemia than to hypoxia. Auer has described the ultrastructural changes in neurons resulting from experimental hypoglycemia; with increasing duration of hypoglycemia and EEG silence, there are mitochondrial changes, first in dendrites and then in nerve cell soma, followed by nuclear membrane disruption leading to cell death.


Neurology_Adams

Neurology_Adams. Treatment of all forms of hypoglycemia obviously consists of correction of the hypoglycemia at the earliest possible moment. It is not known whether hypothermia or other measures will increase the safety period in hypoglycemia or alter the outcome. Seizures and twitching may not stop with antiepileptic drugs until the hypoglycemia is corrected. Two syndromes have been defined, mainly in diabetics: (1) hyperglycemia with ketoacidosis and (2) hyperosmolar nonketotic hyperglycemia.


Neurology_Adams

Neurology_Adams. Two syndromes have been defined, mainly in diabetics: (1) hyperglycemia with ketoacidosis and (2) hyperosmolar nonketotic hyperglycemia. In diabetic acidosis, the familiar picture is one of dehydration, fatigue, weakness, headache, abdominal pain, dryness of the mouth, stupor or coma, and Kussmaul type of breathing. Usually the condition has developed over a period of days in a patient known or proven to be diabetic. Often, the patient had failed to take a regular insulin dose. The blood glucose level is found to be more than 400 mg/dL, the pH of the blood less than 7.20, and the bicarbonate less than 10 mEq/L. Ketone bodies and b-hydroxybutyric acid are elevated in the blood and urine, and there is marked glycosuria. The prompt administration of insulin and repletion of intravascular volume correct the clinical and chemical abnormalities over a period of hours.


Neurology_Adams

Neurology_Adams. A small group of patients with diabetic ketoacidosis, such as those reported by Young and Bradley, develop deepening coma and cerebral edema as the elevated glucose is corrected. Mild cerebral edema is commonly observed in children during treatment with fluids and insulin (Krane et al). Prockop attributed this condition to an accumulation of fructose and sorbitol in the brain. The latter substance, a polyol that is formed during hyperglycemia, crosses membranes slowly, but once it does so, is said to cause a shift of water into the brain and an intracellular edema. However, according to Fishman (1974), the increased polyols in the brain in hyperglycemia are not present in sufficient concentration to be important osmotically, though they may induce other metabolic effects related to the encephalopathy. These are matters of conjecture, as the increase of polyols has never been found. The brain edema in this condition is probably a result of reversal of the osmolality gradient from blood


Neurology_Adams

Neurology_Adams. These are matters of conjecture, as the increase of polyols has never been found. The brain edema in this condition is probably a result of reversal of the osmolality gradient from blood to brain, which occurs with rapid correction of hyperglycemia.


Neurology_Adams

Neurology_Adams. The pathophysiology of the cerebral disorder in diabetic ketoacidosis is not fully understood. No consistent cellular pathology of the brain has been identified in the cases we have examined. Factors such as ketosis, tissue acidosis, hypotension, hyperosmolality, and hypoxia have not been identified. Attempts at therapy by the administration of urea, mannitol, salt-poor albumin, and dexamethasone are usually unsuccessful, though recoveries are reported.


Neurology_Adams

Neurology_Adams. In hyperosmolar nonketotic hyperglycemia, the blood glucose is extremely high, more than 600 mg/dL, but ketoacidosis does not develop, or if it does develop, it is mild. Osmolality is usually in excess of 330 mOsm/L. There is also hemoconcentration and prerenal azotemia. Appreciation of the neurologic syndrome is generally credited to Wegierko, who published descriptions of it in 1956 and 1957. Most of the patients are elderly diabetics but some were not previously known to have been diabetic. An infection, enteritis, pancreatitis, dehydration, or a drug known to upset diabetic control (thiazides, corticosteroids, and phenytoin) leads to polyuria, fatigue, confusion, stupor, and coma. Often the syndrome arises in conjunction with the combined use of corticosteroids and phenytoin (which inhibits insulin release), for example, in elderly patients with brain tumors. The use of osmotic diuretics enhances the risk.


Neurology_Adams

Neurology_Adams. Seizures and focal signs such as a hemiparesis, a hemisensory defect, choreoathetosis, or a homonymous visual field defect are more common than in any other metabolic encephalopathy and may erroneously suggest the possibility of a stroke. Fluids should be replaced cautiously, using isotonic saline and potassium. Correction of the markedly elevated blood glucose requires relatively small amounts of insulin, since these patients often do not have a high degree of insulin resistance. Hepatic Stupor and Coma (Hepatic, or


Neurology_Adams

Neurology_Adams. Chronic hepatic insufficiency with portosystemic shunting of blood is punctuated by episodes of stupor, coma, and other neurologic symptoms—a state referred to as hepatic stupor, coma, or encephalopathy. It was clearly delineated by Adams and Foley over 70 years ago. This state complicates all varieties of liver disease and is unrelated to jaundice or ascites. Any form of shunting, even without hepatic disease, such as surgical portal–systemic shunt (Eck fistula) is attended by the same clinical picture (see further on). There are also a number of hereditary hyperammonemic syndromes, usually first apparent in infancy or childhood (discussed extensively in Chap. 36) that lead to episodic coma with or without seizures. In all these states, it is common for an excess of protein derived from the diet or from gastrointestinal hemorrhage to induce or worsen the encephalopathy. Additional predisposing factors are hypoxia, hypokalemia, metabolic alkalosis, excessive diuresis, use of sedative


Neurology_Adams

Neurology_Adams. the diet or from gastrointestinal hemorrhage to induce or worsen the encephalopathy. Additional predisposing factors are hypoxia, hypokalemia, metabolic alkalosis, excessive diuresis, use of sedative hypnotic drugs, and constipation. A special from of the syndrome in epilepsy patients exposed to valproate; confusion and ataxia may occur acutely or subacutely in these patients (Gomcelli et al). Reye syndrome following viral infections in children, now infrequent, was also associated with very high levels of ammonia in the blood and encephalopathy (see further on).


Neurology_Adams

Neurology_Adams. The clinical picture of acute, subacute, or chronic hepatic encephalopathy consists of a derangement of consciousness, presenting first as mental slowing and confusion, occasionally with hyperactivity, followed by progressive drowsiness, stupor, and coma. The confusional state is combined with a characteristic intermittency of sustained muscle contraction; this phenomenon, which was originally described in patients with hepatic stupor by Adams and Foley and called asterixis (from the Greek sterixis, a “fixed position”). It is now recognized as a sign of various metabolic encephalopathies but is most prominent in this disorder (see Chap. 4). It is conventionally demonstrated by having the patient hold his arms outstretched with the wrists extended, but the same tremor can be elicited by any sustained posture, including that of the protruded tongue. We have seen patients in whom asterixis of the large antigravity muscles (e.g., iliopsoas or quadriceps) causes falling. A variable,


Neurology_Adams

Neurology_Adams. by any sustained posture, including that of the protruded tongue. We have seen patients in whom asterixis of the large antigravity muscles (e.g., iliopsoas or quadriceps) causes falling. A variable, fluctuating rigidity of the trunk and limbs, grimacing, suck and grasp reflexes, exaggeration or asymmetry of tendon reflexes, Babinski signs, and focal or generalized seizures round out the clinical picture in a few patients.


Neurology_Adams

Neurology_Adams. The EEG is a sensitive and reliable indicator of impending coma, becoming abnormal during the earliest phases of the disordered mental state. Foley et al noted an EEG abnormality consisting of paroxysms of bilaterally synchronous slow or triphasic waves in the delta range, which at first predominate frontally and are interspersed with alpha activity and later, as the coma deepens, displace all normal activity (see Fig. 2-7J). A few patients show only random high-voltage asynchronous slow waves.


Neurology_Adams

Neurology_Adams. This syndrome of hepatic encephalopathy is remarkably diverse in its course and evolution. It usually appears over a period of days to weeks and may terminate fatally; or, with appropriate treatment, the symptoms may regress and then fluctuate in severity for several weeks or months. Persistent hepatic coma of the latter type proves fatal in about half of patients (Levy et al). In many patients, the syndrome is relatively mild and does not evolve beyond the stage of mental dullness and confusion, with asterixis and EEG changes. In yet others, a subtle disorder of mood, personality, and intellect may be protracted over a period of many months or even years; this chronic but nevertheless reversible mental disturbance need not be associated with overt clinical signs of liver failure (jaundice and ascites) or other neurologic signs. Characteristically in these patients, an extensive portal–systemic collateral circulation can be demonstrated (hence the term portal–systemic encephalopathy)


Neurology_Adams

Neurology_Adams. and ascites) or other neurologic signs. Characteristically in these patients, an extensive portal–systemic collateral circulation can be demonstrated (hence the term portal–systemic encephalopathy) and an association established between the mental disturbance and an intolerance to dietary protein as well as raised blood ammonia levels (Summerskill et al).


Neurology_Adams

Neurology_Adams. The diversion of blood from the portal system into the vena cava after ligation of the portal veins was first performed in dogs by Eck in 1877. Probably the first and certainly most striking example in man was the case of pure “Eck” fistula reported by McDermott and Adams, in which a portacaval shunt was created during the removal of a pancreatic tumor. The liver was normal. Episodic coma occurred thereafter whenever dietary protein increased. Consciousness was restored on a protein-free diet, and coma could be induced again by ammonium chloride. Postmortem examination 2 years later confirmed the normal liver and showed cerebral changes of hepatic encephalopathy, as described below.


Neurology_Adams

Neurology_Adams. Finally, there is a group of patients (most of whom have experienced repeated attacks of hepatic coma) in whom an irreversible mild dementia and a disorder of posture and movement (grimacing, tremor, dysarthria, ataxia of gait, choreoathetosis) gradually appear. This condition of chronic acquired hepatocerebral degeneration must be distinguished from other dementing and extrapyramidal syndromes (see further on). A few cases of isolated spastic paraplegia (so-called hepatic myelopathy, or more correctly hepatic paraplegia) have been described. Pant et al attributed the syndrome to a loss of Betz cells in the frontal cortex; in other words, a restricted encephalopathy seen in some patients with portal-systemic encephalopathy. Indeed, the spasticity of the legs, increased tendon reflexes, and Babinski signs that are found with portal- systemic encephalopathy, suggest that “hepatic paraparesis” is a common feature.


Neurology_Adams

Neurology_Adams. The MRI in chronic portal-systemic encephalopathy often demonstrates symmetric high signal intensity on T1-weighted sequences in the globus pallidus, likely the result of manganese deposition. In acute portal-systemic encephalopathy, regions of abnormal T2 hyperintensity throughout the cerebral hemispheres are seen, most often involving the insula, thalamus, and cingulate. The concentrations of blood NH3, particularly if measured repeatedly in arterial blood samples, usually are well in excess of 200 mg/dL, and the severity of the neurologic and EEG disorders roughly parallels the ammonia levels. With treatment, a fall in the NH3 levels precedes clinical improvement.


Neurology_Adams

Neurology_Adams. The striking finding by Adams and Foley in patients who died in a state of hepatic coma was a diffuse increase in the number and size of the protoplasmic astrocytes in the deep layers of the cerebral cortex, lenticular nuclei, thalamus, substantia nigra, cerebellar cortex, and red, dentate, and pontine nuclei, with little or no visible alteration in the nerve cells or other parenchymal elements. With periodic acid-Schiff (PAS) staining, the astrocytes were seen to contain glycogen inclusions. These abnormal glia cells are generally referred to as Alzheimer type II astrocytes, having been described originally in 1912 by von Hosslin and Alzheimer in a patient with Westphal-Strümpell pseudosclerosis (or Wilson disease). These astrocytes have been studied by electron microscopy in rats with surgically created portacaval shunts (Cavanagh; Norenberg); the cells show a number of striking abnormalities—swelling of their terminal processes, cytoplasmic vacuolation (distended sacs of rough


Neurology_Adams

Neurology_Adams. surgically created portacaval shunts (Cavanagh; Norenberg); the cells show a number of striking abnormalities—swelling of their terminal processes, cytoplasmic vacuolation (distended sacs of rough endoplasmic reticulum), formation of folds in the basement membrane around capillaries, and an increase in both the number of mitochondria and enzymes that catabolize ammonia. Also, some degeneration in myelinated nerve fibers in the neuropil and an increase in the cytoplasm of oligodendrocytes are seen. In chronic cases, neuronal loss in the deep layers of the cerebral and cerebellar cortex and lenticular nuclei is found, as well as vacuolization of tissue (possibly astrocytic) resembling the lesions of Wilson disease.


Neurology_Adams

Neurology_Adams. The ubiquitous astrocytic alterations occur to some degree in all patients who die of progressive liver failure and the degree of glial abnormality corresponds generally to the intensity and duration of the neurologic disorder. Possibly, the astrocytic changes affect the synaptic activities of the neurons. The clinical and EEG features of hepatic encephalopathy as well as the astrocytic hyperplasia are more or less specific features of this metabolic disorder. Nevertheless, taken together in a setting of liver failure, they constitute a distinctive clinicopathologic entity. Pathogenesis of Hepatic Encephalopathy


Neurology_Adams

Neurology_Adams. The most plausible hypothesis relates hepatic coma to an abnormality of nitrogen metabolism, wherein ammonia, which is formed in the bowel by the action of urease-containing organisms on dietary protein, is carried to the liver in the portal circulation but fails to be converted into urea because of hepatocellular disease, portal– systemic shunting of blood, or both. As a result, excess NH3 reaches the systemic circulation, where it interferes with cerebral metabolism in a way that is not fully understood. The ammonia theory best explains the basic neuropathologic change. Because the brain is lacking in urea cycle enzymes, Norenberg has proposed that the hypertrophy of the astrocytic cytoplasm and proliferation of mitochondria and endoplasmic reticulum, as well as the increase in the astroglial glutamic dehydrogenase activity, all reflect heightened metabolic activity of these systems within astrocytes associated with ammonia detoxification. Removal of brain ammonia depends on the


Neurology_Adams

Neurology_Adams. glutamic dehydrogenase activity, all reflect heightened metabolic activity of these systems within astrocytes associated with ammonia detoxification. Removal of brain ammonia depends on the formation of glutamine, a reaction that is catalyzed by the ATP-dependent enzyme glutamine synthetase, which is compartmentalized to astrocytes. It has been shown in experimental animals that hyperammonemia leads to a depletion of ATP in midbrain reticular nuclei. Whether this is the primary cause of cerebral dysfunction has not been resolved.


Neurology_Adams

Neurology_Adams. Numerous alternative theories have been suggested. One is that CNS function in cirrhotic patients is impaired by phenols or short-chain fatty acids derived from the diet or from bacterial metabolism of carbohydrate. Another theory holds that biogenic amines (e.g., octopamine), which arise in the gut and bypass the liver, act as false neurotransmitters, displacing norepinephrine and dopamine (Fischer and Baldessarini). Zieve has presented evidence that mercaptans (methanethiol, methionine), which are also generated in the gastrointestinal tract and removed by the liver, act in conjunction with NH3 to produce hepatic encephalopathy. This theory and others have been largely discounted; they are the subject of reviews by Butterworth and coworkers, by Zieve, by Rothstein and Herlong, and by Jones and Basile, to which the reader is referred for detailed information.


Neurology_Adams

Neurology_Adams. Also, manganese has emerged as a potential neurotoxin in the pathogenesis of hepatic encephalopathy (Kreiger et al; Pomier-Layrargues et al). In patients with chronic liver disease and with spontaneous or surgically induced portal–systemic shunts, manganese accumulates in the serum and in the brain, more specifically in the pallidum. This accumulation is readily discernible as a pallidal signal hyperintensity on T1-weighted MRI, as mentioned above. Following liver transplantation, there is normalization of these MRI changes and of the associated extrapyramidal symptoms. The effects of manganese chelation on such patients have not been well studied and the mechanisms of accumulated manganese in the pathogenesis of hepatic encephalopathy are not known. It is clear, therefore, that any theory of hepatic encephalopathy must incorporate the cerebral effects of hyperammonemia.


Neurology_Adams

Neurology_Adams. For some time, it has been known that hepatic encephalopathy is associated with increased activity of the inhibitory transmitter GABA in the cerebral cortex. It has also been observed that increased gabanergic neurotransmission may result from substances that inhibit the binding of endogenous benzodiazepine-like compounds to their receptors (Basile et al). Furthermore, these antagonists are found to have some clinical effect—transient arousal in patients with hepatic encephalopathy. The actions of benzodiazepines are mediated by these receptors; hence the designation GABA-benzodiazepine theory. The practicality of using benzodiazepine receptor antagonists, which are short-acting and reversible (e.g., flumazenil) in the treatment of hepatic encephalopathy, remains to be determined (see Mullen), but they offer an interesting diagnostic test.


Neurology_Adams

Neurology_Adams. Until recently, the ammonia and the gabanergic-benzodiazepine hypotheses of the pathogenesis of hepatic encephalopathy had appeared to be unrelated. However, there is evidence, reviewed by Jones and Basile, that ammonia, even in the modestly elevated concentrations that occur in liver failure, inhibits metabolism of GABA by the astrocytes and enhances gabanergic neurotransmission—a concept that unifies hyperammonemia and the neurotransmitter change. Furthermore, the aforementioned glial abnormality may be the explanation for the disorder of the blood-brain barrier that leads to the brain swelling that is seen in some rapidly developing cases of portal-systemic encephalopathy, the prototype for which is the now infrequent Reye syndrome. A parallel astrocytic dysfunction may lead to disruption of the blood–brain barrier and the brain swelling that is known to occur in cases of acute liver failure.


Neurology_Adams

Neurology_Adams. Despite the incompleteness of our understanding of the role of disordered ammonia metabolism in the genesis of hepatic coma, an awareness of this relationship has provided the few effective means of treating this disorder: restriction of dietary protein; reduction of bowel flora by oral administration of neomycin or kanamycin, which suppresses the urease-producing organisms in the bowel; and the use of enemas. The mainstay of treatment has been oral lactulose, an inert sugar that is metabolized by colonic bacteria that produce hydrogen ions and shifts ammonia to ammonium, a nontoxic product that is eliminated in the stool. The past use of oral neomycin carried a risk of renal damage and ototoxicity and has therefore been replaced by rifaximin, a minimally absorbed antibiotic that has less risk. This antibiotic has also been shown by Bass and coworkers to be highly effective in preventing episodic hepatic encephalopathy in tenuously compensated patients. The salutary effect of these


Neurology_Adams

Neurology_Adams. risk. This antibiotic has also been shown by Bass and coworkers to be highly effective in preventing episodic hepatic encephalopathy in tenuously compensated patients. The salutary effect of these therapeutic measures, the common attribute of which is the lowering of the blood NH3, further supports the theory of ammonia intoxication. Ultimately, in cases of intractable liver failure, transplantation becomes a treatment of last resort.


Neurology_Adams

Neurology_Adams. Other treatments with lesser value include bromocriptine, the aforementioned diazepine antagonist flumazenil, and keto analogues of essential amino acids. Theoretically, the keto analogues should provide a nitrogen-free source of essential amino acids (Maddrey et al), a treatment that has been largely abandoned, and bromocriptine, a dopamine agonist, should enhance dopaminergic transmission (Morgan et al) but its mechanism is not known. Administration of branched-chain amino acids may result in improvement in mental status but their effects have been variable and associated with an increased mortality (Naylor et al). The transient beneficial effect of the benzodiazepine antagonist flumazenil has already been mentioned; it is used as well as a diagnostic test.


Neurology_Adams

Neurology_Adams. In acute hepatitis, confusional, delirious, and comatose states also occur but their mechanisms are still unknown. Blood NH3 may be elevated but usually not to a degree that would be expected to cause encephalopathy. Severe acute hepatic failure may cause hypoglycemia, which contributes to the encephalopathy and often presages a fatal outcome but the levels of glucose typically detected do not provide an explanation for the encephalopathy.


Neurology_Adams

Neurology_Adams. Cerebral edema is a prominent finding in cases of fulminant hepatic failure and is the main cause of death in patients awaiting liver transplantation. The cerebral edema in these circumstances appears to be related to the rapidity of rise of blood ammonia, but it probably depends as well on additional metabolic derangements that complicate acute liver failure including glial cell failure with consequent incompetence of the blood–brain barrier. The combination of rapidly evolving hepatic failure and massive cerebral edema is similar to that observed in the Reye syndrome, described below.


Neurology_Adams

Neurology_Adams. CT and MRI are effective means of detecting cerebral edema in patients with fulminant hepatic failure, and according to Wijdicks and colleagues, the degree of cerebral swelling is roughly proportional to the severity of encephalopathy. Because patients with fulminant hepatic failure can survive liver transplantation with few or no neurologic deficits, it is important to recognize cerebral edema before the stage of stupor and increased intracranial pressure has been established. Short of transplantation, death in these cases may sometimes be prevented by monitoring the intracranial pressure (as outlined by Lidofsky et al) and administering osmotic diuretics and hyperventilation, as detailed in Chaps. 29 and 34 for the treatment of intracranial hypertension. Some survivors are nonetheless left with cerebral damage from raised intracranial pressure.


Neurology_Adams

Neurology_Adams. An additional issue that arises in assessing cerebral dysfunction in patients with liver disease is the possibility of adverse effects of medications. Individuals with hepatitis C who had in the past been treated with interferon-alpha may have developed a spectrum of problems ranging from subtle cognitive impairment to a subacutely worsening headache, vomiting, altered consciousness, and focal neurologic findings. The milder syndromes are associated with no or few MRI-visible lesions but the severe ones are usually accompanied by signal changes in the white matter of the occipital lobes and elsewhere (posterior leukoencephalopathy).


Neurology_Adams

Neurology_Adams. This is a special type of nonicteric hepatic encephalopathy occurring in children and adolescents and characterized by acute brain swelling in association with fatty infiltration of the viscera, particularly the liver. Although individual cases of this disorder had been described for many years, its recognition as a clinical-pathologic entity dates from 1963, when a large series was reported from Australia by Reye and colleagues and from the United States by


Neurology_Adams

Neurology_Adams. Johnson and coworkers. The disorder tended to occur in outbreaks (286 cases were reported to the Centers for Disease Control during a 4-month period in 1974). Mainly, these outbreaks were observed in association with influenza B virus and varicella infections, but a variety of other viral infections were implicated (influenza A, echovirus, reovirus, rubella, rubeola, herpes simplex, Epstein-Barr virus). Later it became apparent that the toxic or adjuvant effects of aspirin given during these infections played an important role in producing the disease. Today, only occasional instances of Reye syndrome are observed now that the association with aspirin administration has become widely known and its use in children with viral infections has been interdicted.


Neurology_Adams

Neurology_Adams. Most patients are children, boys and girls being equally affected, but rare instances are known in infants (Huttenlocher and Trauner) and young adults. In most cases, the encephalopathy is preceded for several days to a week by fever, symptoms of upper respiratory infection, and protracted vomiting. These are followed by the rapid evolution of stupor and coma, associated in many cases with focal and generalized seizures, signs of sympathetic overactivity (tachypnea, tachycardia, mydriasis), decorticate and decerebrate rigidity, and loss of pupillary, corneal, and vestibuloocular reflexes. One or two such cases were included in the series of acute “toxic encephalopathy” reported by Lyon and colleagues (see “Acute Toxic Encephalopathy” in Chap. 31). In infants, respiratory distress, tachypnea, and apnea are the most prominent features.


Neurology_Adams

Neurology_Adams. The liver may be greatly enlarged, often extending to the pelvis and providing an important diagnostic clue as to the cause of the cerebral changes. Initially there is a metabolic acidosis, followed by a respiratory alkalosis (rising arterial pH and falling Pco2). The CSF is usually under increased pressure and is acellular; glucose values may be low, reflecting the hypoglycemia. The serum ALT, coagulation times, and blood ammonia are increased, sometimes to an extreme degree. The EEG is characterized by diffuse arrhythmic delta activity, progressing to electrocerebral silence in patients who fail to survive. CT and MRI show the cerebral swelling but are difficult to interpret in these young individuals, who lack any adult brain atrophy.


Neurology_Adams

Neurology_Adams. The major pathologic findings are cerebral edema, often with cerebellar herniation, and infiltration of hepatocytes with fine droplets of fat (mainly triglycerides); the renal tubules, myocardium, skeletal muscles, pancreas, and spleen are infiltrated to a lesser extent. There are no inflammatory lesions in the brain, liver, or other organs. There is not full agreement as to the pathogenesis of this disorder and the mechanism of aspirin toxicity but mitochondrial dysfunction has been implicated.


Neurology_Adams

Neurology_Adams. In a series of children with blood ammonia levels greater than 500 mg/dL who were treated during the years 1967 to 1974, Shaywitz and colleagues reported a mortality of 60 percent. Once the child became comatose, death was almost inevitable. In more recent years, early diagnosis and initiation of treatment before the onset of coma have reduced the fatality rate to 5 to 10 percent. Treatment consists of the following measures: temperature control with a cooling blanket; nasotracheal intubation and controlled ventilation to maintain Pco2 below 32 mm Hg; intravenous glucose covered by insulin to maintain blood glucose at 150 to 200 mg/dL; administration of lactulose, neomycin enemas, and hemodialysis to directly lower the NH3 concentration; control of intracranial pressure by means of continual monitoring and the use of hypertonic solutions (see Chap. 30); and the maintenance of fluid and electrolyte balance (Trauner). Upon recovery, cerebral function returns to normal unless there had


Neurology_Adams

Neurology_Adams. monitoring and the use of hypertonic solutions (see Chap. 30); and the maintenance of fluid and electrolyte balance (Trauner). Upon recovery, cerebral function returns to normal unless there had been deep and prolonged coma or protracted elevation of intracranial pressure.


Neurology_Adams

Neurology_Adams. Episodic confusion and stupor and other neurologic symptoms may accompany any form of severe renal disease—acute or chronic. The cerebral symptoms attributable to uremia (first described by Addison in 1832) are discerned in normotensive individuals in whom renal failure develops rapidly. Apathy, fatigue, inattentiveness, and irritability are usually the initial symptoms; later, there is confusion, dysarthria, tremor, and asterixis. Infrequently, this takes the form of a toxic psychosis, with hallucinations, delusions, insomnia, or catatonia (Marshall). These symptoms characteristically fluctuate from day to day, or even from hour to hour. In some patients, especially those who become anuric, symptoms may come on abruptly and progress rapidly to a state of stupor and coma. In others, in whom uremia develops more gradually, mild visual hallucinations and a disorder of attention may persist for several weeks in relatively pure form. The EEG becomes diffusely and irregularly slow and may


Neurology_Adams

Neurology_Adams. uremia develops more gradually, mild visual hallucinations and a disorder of attention may persist for several weeks in relatively pure form. The EEG becomes diffusely and irregularly slow and may remain so for several weeks after the institution of dialysis. The CSF pressure is normal and the protein is not elevated unless there is a uremic or diabetic neuropathy. In several reports, meningismus and a low-grade mononuclear pleocytosis have been mentioned (Merritt and Fremont-Smith), but we have not encountered this.


Neurology_Adams

Neurology_Adams. In acute renal failure, clouding of the sensorium is practically always associated with a variety of motor phenomena. These usually occur early in the course of the encephalopathy, sometimes when the patient is still mentally clear. The patient begins to twitch and jerk and may convulse. The myoclonic twitches involve parts of muscles, whole muscles, or entire limbs and are lightning-quick, arrhythmic, and asynchronous on the two sides of the body; they are incessant during both wakefulness and sleep. At times the movements resemble those of chorea or an arrhythmic tremor; asterixis is also readily evoked. The motor phenomena are often difficult to classify. Our predecessor authors described the condition as a uremic twitch-convulsive syndrome.


Neurology_Adams

Neurology_Adams. The resemblance of uremic encephalopathy to hepatic and other metabolic encephalopathies has been stressed by Raskin and Fishman, yet we are more impressed with differences than with similarities. When the twitch-convulsive syndrome is observed in association with other diseases such as widespread neoplasia, delirium tremens, diabetic coma, and lupus erythematosus, the causative factor of renal failure is usually discovered. As the uremia worsens, the patient lapses into a quiet coma. Unless the accompanying metabolic acidosis is corrected, Kussmaul breathing appears and gives way to Cheyne-Stokes breathing and death.


Neurology_Adams

Neurology_Adams. As the uremia worsens, the patient lapses into a quiet coma. Unless the accompanying metabolic acidosis is corrected, Kussmaul breathing appears and gives way to Cheyne-Stokes breathing and death. Encephalopathy and coma in the patient with renal failure may, of course, be a result of disorders other than uremia itself. Because of the similarity of this syndrome to tetany, measurement should be made of serum calcium and magnesium—and, of course, hypocalcemia and hypomagnesemia do occur in uremia. But often the values for these ions are normal or near normal, and the administration of calcium and magnesium salts has little effect. The altered excretion of drugs leads to their accumulation, sometimes evoking excessive sedation. Subdural and intracerebral hemorrhages may complicate uremia (and dialysis) because of clotting defects and hypertension; and uremic patients are prone to infections, including meningitis.


Neurology_Adams

Neurology_Adams. Because chronic uremia is so frequently associated with hypertension, a major problem also arises in distinguishing the cerebral effects of uremia from those of severe and accelerated hypertension. Volhard was the first to make this distinction; he introduced the term pseudouremia to designate the cerebral effects of malignant hypertension and to separate them from true uremia. The preferable term, hypertensive encephalopathy, was first used by Oppenheimer and Fishberg. However, the myoclonic-twitch syndrome is not a component of hypertensive encephalopathy. The clinical picture of the latter disorder and its pathophysiology are discussed in “Hypertensive Encephalopathy and Posterior Reversible Encephalopathy Syndrome” in Chap. 33.


Neurology_Adams

Neurology_Adams. Opinions vary widely as to the biochemical basis of uremic encephalopathy and the twitch-convulsive syndrome. Restoration of renal function completely corrects the neurologic syndrome, attesting to the absence of structural change and a functional disorder of subcellular type. Whether caused by the retention of organic acids, elevation of phosphate in the CSF (claimed by Harrison et al), or the action of urea or other toxins, among them parathyroid hormone, has never been settled. The data supporting the causative role of urea itself are also ambiguous, just as they are for other putative endogenous agents (see Bolton and Young (1990) and the review by Burn and Bates). However, it can be stated that urea itself is not the sole inductive agent, as its infusion does not produce the syndrome in humans or animals.


Neurology_Adams

Neurology_Adams. It would appear that every level of the CNS is affected in uremia, from spinal cord to cerebrum. Cellular changes in the brain or spinal cord are limited to mild hyperplasia of protoplasmic astrocytes in some cases, but never of the degree observed in hepatic encephalopathy. Cerebral edema is notably absent. In fact, CT and MRI regularly show an element of cerebral shrinkage. A peripheral neuropathy is also a common complication of uremia and is considered in Chap. 43.


Neurology_Adams

Neurology_Adams. Improvement of encephalopathic symptoms may not be evident for 1 or 2 days after institution of dialysis. Convulsions, which occur in about one-third of cases, often preterminally, may be resistant to treatment until the uremia is addressed. However, some seizures may be suppressed with relatively low-plasma concentrations of antiepileptic drugs, the reason being that serum albumin is depressed in uremia, increasing the unbound, therapeutically active portion of a drug. If there are severe associated metabolic disturbances, such as hyponatremia, the seizures may be difficult to control. One must be cautious in prescribing any of a large number of drugs in the face of renal failure, for inordinately high, toxic blood levels may result. Examples that affect the nervous system are aminoglycoside antibiotics (vestibular damage); furosemide (cochlear damage); and nitrofurantoin, isoniazid, and hydralazine (peripheral nerve damage).


Neurology_Adams

Neurology_Adams. This term refers to a group of symptoms that may occur during and following hemodialysis or peritoneal dialysis as a by-product of some degree of cerebral edema. The symptoms include headache, nausea, muscle cramps, nervous irritability, agitation, drowsiness, and convulsions. The headache, which may be bilateral and throbbing and resemble common migraine, develops in approximately 70 percent of patients, whereas the other symptoms are observed in 5 to 10 percent, usually in those undergoing rapid dialysis or in the early stages of a dialysis program. The symptoms tend to occur in the third or fourth hour of dialysis and last for several hours. Sometimes they appear 8 to 48 h after the completion of dialysis. Originally, these symptoms were attributed to the rapid lowering of serum urea, leaving the brain with a higher concentration of urea than the serum and resulting in a shift of water into the brain to equalize the osmotic gradient (reverse urea syndrome). Now it is believed that


Neurology_Adams

Neurology_Adams. leaving the brain with a higher concentration of urea than the serum and resulting in a shift of water into the brain to equalize the osmotic gradient (reverse urea syndrome). Now it is believed that the shift of water into the brain is akin to water intoxication and is a result of the inappropriate secretion of antidiuretic hormone.


Neurology_Adams

Neurology_Adams. The symptoms of subdural hematoma, which in the past occurred in 3 to 4 percent of patients undergoing dialysis, now being less frequent, may still be mistakenly attributed to the disequilibrium syndrome. This is a subacutely progressive syndrome that in the past complicated chronic hemodialysis. Characteristically, the condition begins with a hesitant, stuttering dysarthria and aphasia, to which are added facial and then generalized myoclonus, focal and generalized seizures, personality and behavioral changes, and intellectual decline. The EEG is invariably abnormal, taking the form of paroxysmal and sometimes periodic sharp-wave or spike-and-wave activity (up to 500 mV and lasting 1 to 20 s), intermixed with abundant theta and delta activity. The CSF is normal except occasionally for increased protein.


Neurology_Adams

Neurology_Adams. At first the myoclonus and speech disorders are intermittent, occurring during or immediately after dialysis and lasting for only a few hours, but gradually they become more persistent and eventually permanent. Once established, the syndrome is usually steadily progressive over a 1to 15-month period (average survival of 6 months in the 42 cases analyzed by Lederman and Henry). A characteristic feature is a transient improvement in speech with the administration of intravenous diazepines.


Neurology_Adams

Neurology_Adams. The neuropathologic changes are said to be subtle and consist of a mild degree of microcavitation of the superficial layers of the cerebral cortex. Although the changes are diffuse, they have been found in one study to be more severe in the left (dominant) hemisphere than in the right and more severe in the left frontotemporal operculum than in the surrounding cortex (Winkelman and Ricanati). The disproportionate affection of the left frontotemporal opercular cortex putatively explains the distinctive disorder of speech and language. In the one case, we have studied carefully, we could not be certain of any microscopic changes.


Neurology_Adams

Neurology_Adams. The most plausible view of the pathogenesis of dialysis encephalopathy is that it represented a form of aluminum intoxication (Alfrey et al), the aluminum being derived from the dialysate or from orally administered aluminum gels. In recent years, this disorder has disappeared, the result, in all likelihood, of the universal practice of purifying the water used in dialysis and thereby removing aluminum from the dialysate. This subject has been reviewed by Parkinson and coworkers. Complications of Renal Transplantation


Neurology_Adams

Neurology_Adams. The risk in immunosuppressed persons of developing a primary lymphoma of the brain or progressive multifocal leukoencephalopathy is well known and has been mentioned in previous chapters. An entirely different encephalopathy that is marked by widespread visual symptoms and edema of the cerebral white matter, evident on the MRI, but mainly occipital, occurs after the administration of cyclosporine and other immunosuppressant drugs. These imaging features of reversible posterior leukoencephalopathy or posterior reversible encephalopathy syndrome (PRES; see Chaps. 33 and 41) are not specific, being seen also in patients with hypertensive encephalopathy, eclampsia, intrathecal methotrexate administration, and other conditions (see Table 41-1 and Figs. 33-35 and 41-2) all of which are probably linked by endothelial dysfunction of cerebral vessels. Systemic fungal infections had in the past been found at autopsy in approximately 45 percent of patients who had had renal transplants and long


Neurology_Adams

Neurology_Adams. linked by endothelial dysfunction of cerebral vessels. Systemic fungal infections had in the past been found at autopsy in approximately 45 percent of patients who had had renal transplants and long periods of immunosuppressive treatment; in about one-third of these patients, the CNS was involved. Cryptococcus, Listeria, Aspergillus, Candida, Nocardia, and Histoplasma were the usual organisms. Recent experience suggests a far lower rate of infection but it remains a threat. Other CNS infections that have complicated transplantation are toxoplasmosis and cytomegalovirus (CMV) inclusion disease.


Neurology_Adams

Neurology_Adams. We have found examples of Wernicke-Korsakoff disease and central pontine myelinolysis in uremic patients. A bleeding diathesis may result in subdural or cerebral hemorrhage, as already mentioned.


Neurology_Adams

Neurology_Adams. Bolton and Young (1993) have drawn attention to the frequent occurrence, in severely septic patients, of a drowsy or confusional state that is reversible and not explained by hepatic, pulmonary, or renal failure, electrolyte imbalance, hypotension, drug intoxication, or a primary lesion of the brain. They called the condition “septic encephalopathy.” According to their surveys, 70 percent of patients become disoriented and confused within hours of the onset of severe systemic infection; in a few cases, this state may progress to stupor and coma. Notably there are no signs of asterixis, myoclonus, or focal cerebral disorder but paratonia is common, as is the later development of a polyneuropathy. Rapid changes in water balance may occur, leading to the type of osmotic demyelination discussed below.


Neurology_Adams

Neurology_Adams. The encephalopathic state that occurs with severe systemic infection may also develop independently of sepsis, as a component of a syndrome of multiple organ failure and, according to some authors, a complication of widespread cutaneous burns (Aikawa et al). Others have questioned the validity of this last category and have instead found explanatory electrolyte disorders (particularly hyponatremia), sepsis, or multiple brain abscesses.


Neurology_Adams

Neurology_Adams. It has been useful in clinical work to distinguish these encephalopathies of infection and multiorgan failure from those caused by isolated hepatic or renal disease. The lack of a biochemical marker and the confounding effects of hypotension during sepsis (septic shock) leave doubt as to pathogenesis. Altered phenylalanine metabolism and circulating cytokines have been proposed as causes, without firm evidence. Of interest in 2 of our fatal cases was the presence of brain purpura, but this has otherwise been an infrequent finding. Here, the white matter of the cerebrum and cerebellum was speckled with myriad pericapillary hemorrhages and zones of adjacent necrosis. This pathologic reaction is nonspecific, having also been seen in cases of viral pneumonia, heart failure with morphine overdose, thrombotic thrombocytopenic purpura and arsenic poisoning. Disorders of Sodium, Potassium, and


Neurology_Adams

Neurology_Adams. Disorders of Sodium, Potassium, and Drowsiness, confusion, stupor, and coma, in conjunction with seizures and sometimes with other neurologic deficits, may have as their basis a more or less pure abnormality of electrolyte or water balance. Only brief reference is made here to some of these, such as hypocalcemia, hypercalcemia, hypophosphatemia, and hypomagnesemia, as they are considered in other parts of the text. Hyponatremia and Syndrome of Inappropriate Antidiuretic Hormone


Neurology_Adams

Neurology_Adams. Hyponatremia and Syndrome of Inappropriate Antidiuretic Hormone Hyponatremia is defined as a serum sodium level below 135 mEq/L. The hyponatremic state may be isotonic, hypertonic, or hypotonic, depending on the mechanism of reduced sodium concentration. The hypotonic variety is most common in neurologic practice but one also encounters cases of pseudohyponatremia caused by hyperlipidemia or hyperproteinemia (isotonic), hyperglycemic or mannitol-induced hyponatremia (hypertonic), and also cases of water intoxication. The last of these may be associated with systemic hypovolemic (blood loss, salt wasting), hypervolemic (edematous states such as renal, hepatic or heart failure), or isovolemic states (retention of free water).


Neurology_Adams

Neurology_Adams. Hypotonic isovolemic hypernatremia is most often a result of the syndrome of inappropriate antidiuretic hormone secretion (SIADH). This state is of special importance because it complicates neurologic diseases of many types: head trauma, bacterial meningitis and encephalitis, cerebral infarction, subarachnoid hemorrhage, cerebral and systemic neoplasm, Guillain-Barré syndrome and the effects of certain medications. SIADH is the result of excretion of urine that is hypertonic relative to the plasma. As the hyponatremia develops, there is a decrease in alertness, which progresses through stages of confusion to coma, often with convulsions. As with many other metabolic derangements, the severity of the clinical effect is related to the rapidity of decline in serum Na. Lack of recognition of this state may allow the serum Na to fall to dangerously low levels, 100 mEq/L or lower.


Neurology_Adams

Neurology_Adams. Treatment Most instances of hyponatremia have developed slowly, allowing for maintenance of brain volume by the extrusion from cells of various osmotic substances. Rapid correction of sodium in these circumstances risks a reversal of osmotic gradient and a reduction in brain volume. This, in turn, is associated with a special type of central nervous system demyelination (“osmotic demyelination” and central pontine myelinolysis) discussed below. One’s first impulse is to administer NaCl intravenously, but this must be done cautiously to avoid these complications. Most cases of SIADH respond to the restriction of fluid intake—to 500 mL per 24 h if the serum Na is less than 120 mEq/L and to 1,000 mL per 24 h if less than 130 mEq/L. Even when the Na reaches 130 mEq/L, the fluid intake should not exceed 1,500 mL per 24 h.


Neurology_Adams

Neurology_Adams. 48 h) hyponatremia with stupor or seizures, the mechanisms for maintaining cerebral cellular volume have not yet been engaged and therefore infusion of NaCl is necessary to prevent cerebral edema. The amount of NaCl to be infused can be calculated from the current and the target levels of serum Na by assuming that the infused sodium load is distributed throughout the total body water content (0.6 × weight in kilograms): ([target Na − starting Na] × 0.6) × weight (kg)


Neurology_Adams

Neurology_Adams. The desired volume of normal saline can then be determined by keeping in mind that its sodium concentration is 154 mEq/L and that of 3 percent (hypertonic) saline solution is 513 mEq/L. If hypertonic saline is administered, it is usually necessary to simultaneously reduce intravascular volume with furosemide, beginning with a dose of 0.5 mg/kg intravenously, and to increase the dosage until a diuresis is obtained. (As a rule of thumb, 300 to 500 mL of 3 percent saline, infused rapidly intravenously, will increase the serum sodium concentration by about 1 mEq/L/h for 4 h.) Guidelines to prevent an overly rapid correction of Na are elaborated further on in relation to central pontine myelinolysis (no more rapidly than 10 mmol/L in the first 24 h). Although the syndrome of SIADH is usually self-limiting, it may continue for weeks or months, depending on the type of associated brain disease.


Neurology_Adams

Neurology_Adams. Not all patients with neurologic disorders who manifest hyponatremia have SIADH. Diuretic excess, adrenal insufficiency, and salt wasting also produce hypovolemic hyponatremia as a result of natriuresis. When renal salt wasting is seen in the context of a central neurologic disorder, the process has been termed “cerebral salt wasting” (Nelson et al). Sodium loss in these circumstances is attributable to the production by the heart or brain of a potent polypeptide natriuretic factor. As discussed in Chap. 33, under “Subarachnoid Hemorrhage,” the distinction between SIADH and cerebral salt wasting is of more than theoretical importance, insofar as fluid restriction to correct hyponatremia may be dangerous in patients with salt wasting, particularly in those with vasospasm after ruptured intracranial aneurysms.


Neurology_Adams

Neurology_Adams. Arieff emphasized the hazards of postoperative hyponatremia in a series of 15 patients, all of them women, in whom severe hyponatremia followed elective surgery. About 48 h after these patients had recovered from anesthesia, their serum Na fell markedly, at which point generalized seizures occurred, followed by respiratory arrest. We are more familiar with acutely developing hyponatremia in the context of prostate surgery, where large amounts of hypotonic fluids are routinely administered both intravenously and intravascularly. A similar syndrome is known in instances of overly zealous fluid resuscitation in children with diabetic ketoacidosis. The mechanisms of neurologic deterioration in all of these cases is likely to be brain edema.


Neurology_Adams

Neurology_Adams. An important consideration in the management of severe hyponatremia, as mentioned earlier, is the rapidity with which the abnormality is corrected and the danger of provoking central pontine myelinolysis and related brainstem, cerebellar, and cerebral lesions (extrapontine myelinolysis; osmotic demyelination). These issues are considered below, in the section “Central Pontine Myelinolysis.”


Neurology_Adams

Neurology_Adams. Hypernatremia (Na >155 mEq/L) and dehydration are observed in diabetes insipidus, the neurologic causes of which include head trauma with damage to the pituitary stalk (Chap. 26), and in nonketotic diabetic coma, protracted diarrhea in infants, and the deprivation of fluid intake in the stuporous patient. The last condition is usually associated with a brain lesion that impairs consciousness. Exceptionally, in patients with chronic hydrocephalus, the hypothalamic thirst center is rendered inactive and severe hypernatremia, stupor, and coma may follow a failure to drink. In hypernatremia from any cause, the brain volume is manifestly reduced. Retraction of the cerebral cortex from the dura has been known to rupture a bridging vein and cause a subdural hematoma.


Neurology_Adams

Neurology_Adams. As is true for hyponatremia, the degree of CNS disturbance in hypernatremia is generally related to the rate at which the serum Na rises. Slowly rising values, to levels as high as 170 mEq/L, may be surprisingly well tolerated. Rapid elevations of sodium shrink the brain, especially in infants. Extremely high levels cause impairment of consciousness with asterixis, myoclonus, seizures, and choreiform movements. In addition, muscular weakness, rhabdomyolysis, and myoglobinuria have been reported. In hypernatremia with hyperosmolality, the brain retains its volume more effectively than do other organs by a compensatory mechanism that has been attributed to the presence of “idiogenic osmoles,” possibly glucose, glucose metabolites, and amino acids. The impairment of neuronal function in this state is not understood. Theoretically one would expect neuronal shrinkage and possibly alteration of the synaptic surface of the cell.


Neurology_Adams

Neurology_Adams. The main clinical effect of hypokalemia (≤2.0 mEq/L) is generalized muscular weakness (see Chap. 45). A mild confusional state had been alluded to in the literature but must be very infrequent. The electrolyte condition is readily corrected by adding K to intravenous fluid and infusing it at no more than 4 to 6 mEq/h. Hyperkalemia (>7 mEq/L) also may manifest itself by generalized muscle weakness, although the main effects are changes in the electrocardiogram (ECG), possibly leading to cardiac arrest. Limitation of space permits only brief reference to other metabolic disturbances that may present as episodic confusion, stupor, or coma. The most important members of this group are summarized below.


Neurology_Adams

Neurology_Adams. Hypercalcemia This is defined as an elevation of the serum calcium concentration greater than 10.5 mg/dL. If the serum protein content is normal, Ca levels greater than 12 mg/dL are required to produce neurologic symptoms. However, with low-serum albumin levels, an increased proportion of the serum Ca is in the unbound or ionized form (upon which the clinical effects depend), and symptoms may occur with total serum Ca levels as low as 10 mg/dL. In young persons, the most common cause of hypercalcemia is hyperparathyroidism (either primary or secondary); in older persons, osteolytic bone tumors, particularly meta-static carcinoma and multiple myeloma, are often causative. Less common causes are vitamin D intoxication, prolonged immobilization, hyperthyroidism, sarcoidosis, and decreased calcium excretion (renal failure).


Neurology_Adams

Neurology_Adams. Anorexia, nausea and vomiting, fatigue, and headache are usually the initial symptoms, followed by confusion (rarely a delirium) and drowsiness, progressing to stupor or coma in untreated patients. A history of recent constipation is common. Diffuse myoclonus and rigidity occur occasionally, as do elevations of spinal fluid protein (up to 175 mg/100 mL). Convulsions are uncommon.


Neurology_Adams

Neurology_Adams. Hypocalcemia The usual manifestations are paresthesias, tetany, and seizures. With severe and persistent hypocalcemia, altered mental status in the form of depression, confusion, dementia, or personality change can occur. Anxiety to the point of panic attack is also known. Even coma may result, in which case there may be papilledema as a result of increased intracranial pressure. Aside from the raised pressure, the CSF shows no consistent abnormality. This increase in intracranial pressure may be manifest by headache and papilledema without altered mentation or with visual obscurations. Hypoparathyroidism is discussed again further on, under “Acquired Metabolic Diseases Presenting as Progressive Extrapyramidal Syndromes.”


Neurology_Adams

Neurology_Adams. Other electrolyte and acid–base disorders Severe metabolic acidosis from any cause produces a syndrome of drowsiness, stupor, and coma, with dry skin and Kussmaul breathing. The CNS depression does not correlate with the concentration of ketones. Possibly, there are associated effects on neurotransmitters. It is often not possible to separate the effects of acidosis from those caused by an underlying condition or toxic ingestion.


Neurology_Adams

Neurology_Adams. In infants and children, acidosis may occur in the course of hyperammonemia, isovaleric acidemia, maple syrup urine disease, lactic and glutaric acidemia, hyperglycinemia, and other disorders, which are described in detail in Chap. 36. High-voltage slow activity predominates in the EEG, and correction of the acidosis or elevated ammonia level restores CNS function to normal provided that coma was not prolonged or complicated by hypoxia or hypotension. In uncomplicated acidotic coma, no recognizable neuropathologic change has been observed by light microscopy.


Neurology_Adams

Neurology_Adams. Encephalopathy as a consequence of Addison disease (adrenal insufficiency) may be attended by episodic confusion, stupor, or coma without special identifying features; it is usually precipitated in the addisonian patient by infection or surgical stress. Hemorrhagic destruction of the adrenals in meningococcal meningitis (Waterhouse-Friderichsen syndrome) is another cause. Hypotension and diminished cerebral circulation and hypoglycemia are the most readily recognized metabolic abnormalities; measures that correct these conditions reverse the adrenal crisis in some instances. Laureno (1993) reviewed the various neurologic syndromes that result from electrolytic disorders. Central Pontine Myelinolysis and Other Patterns of Osmotic Demyelination


Neurology_Adams

Neurology_Adams. Adams et al observed a rapidly evolving quadriplegia and pseudobulbar palsy in a young alcoholic man who had entered the hospital 10 days earlier with symptoms of alcohol withdrawal. Postmortem examination several weeks later disclosed a large, symmetrical, essentially demyelinative lesion occupying the greater part of the base of the pons. Over the next 5 years, 3 additional cases (2 alcoholic patients and 1 with scleroderma) were studied clinically and pathologically, and in 1959 these 4 cases were reported by Adams and colleagues under the heading of central pontine myelinolysis (CPM). This term was chosen because it reflects both the main anatomic localization of the disease and its essential pathologic attribute: the remarkable dissolution of the sheaths of myelinated fibers and the sparing of neurons. Once attention was focused on this distinctive lesion, many other reports appeared and it became apparent that other areas of myelin in the brain could be similarly affected. The


Neurology_Adams

Neurology_Adams. sparing of neurons. Once attention was focused on this distinctive lesion, many other reports appeared and it became apparent that other areas of myelin in the brain could be similarly affected. The exact incidence of this disease is not known, but in a series of 3,548 consecutive autopsies in adults, the typical lesion was found in 9 cases, or 0.25 percent (Victor and Laureno).


Neurology_Adams

Neurology_Adams. One is compelled to define this disease in terms of its pathologic anatomy because this stands as its most characteristic feature, but it has been appreciated that the pons is not the only structure that may be affected. Transverse sectioning of the fixed brainstem discloses a grayish discoloration and fine granularity in the center of the base of the pons. The lesion may be only a few millimeters in diameter, or it may occupy almost the entire ventral pons. There is always a rim of intact myelin between the lesion and the surface of the pons. Posteriorly, it may reach and involve the medial lemnisci and, in the most advanced cases, other tegmental structures as well. Rarely, the lesion encroaches on the midbrain but it does not extend as far as the medulla. Identical extrapontine myelinolytic foci in the internal capsule, deep cerebral white matter and corpus callosum may occur independently (“extrapontine myelinolysis”). Exceptionally, symmetrically distributed lesions are found in


Neurology_Adams

Neurology_Adams. foci in the internal capsule, deep cerebral white matter and corpus callosum may occur independently (“extrapontine myelinolysis”). Exceptionally, symmetrically distributed lesions are found in the thalamus, subthalamic nucleus, striatum, amygdaloid nuclei, lateral geniculate body, white matter of the cerebellar folia (Wright et al).


Neurology_Adams

Neurology_Adams. Microscopically, the fundamental abnormality consists of destruction of the myelinated sheaths throughout the lesion, with relative sparing of the axons and intactness of the nerve cells of the pontine nuclei. These changes always begin and are most severe in the geometric center of the pons, where they may proceed to frank necrosis of tissue. Reactive phagocytes and glia cells are in evidence throughout the demyelinative focus, but oligodendrocytes are depleted. Signs of inflammation are conspicuously absent.


Neurology_Adams

Neurology_Adams. This constellation of pathologic findings provides easy differentiation of the lesion from infarction and the inflammatory demyelination of multiple sclerosis and postinfectious encephalomyelitis. Microscopically, the lesion resembles that of Marchiafava-Bignami disease (Chap. 40), with which CPM is rarely associated. In the chronic alcoholic, Wernicke disease is often associated with osmotic demyelination, but the lesions bear no resemblance to one another in terms of topography and histology.


Neurology_Adams

Neurology_Adams. More than half the cases have appeared in the late stages of chronic alcoholism, often in association with Wernicke disease and polyneuropathy. Most cases occur in the context of other serious medical conditions, and diseases with which osmotic demyelination has been conjoined are chronic renal failure being treated with dialysis, hepatic failure, advanced lymphoma, cancer, cachexia from a variety of other causes, severe bacterial infections, dehydration and electrolyte disturbances, acute hemorrhagic pancreatitis, and pellagra. The changes in serum sodium concentration, with which the process is closely aligned, are discussed below. The 2 sexes are affected equally, and the patients do not fall into any one age period. Whereas the cases first reported had occurred in adults, there are now many reports of the disease in children, particularly in those with severe burns (McKee et al).


Neurology_Adams

Neurology_Adams. In many patients there are no symptoms or signs that betray the pontine lesion, presumably because it is so small, extending only 2 to 3 mm on either side of the median raphe and involving only a small portion of the corticopontine or pontocerebellar fibers. In others, its presence is obscured by coma from a metabolic or other associated disease. Prior to the inception of MRI only a minority of cases, exemplified by the first patient observed by Adams et al, were recognized during life. In this patient, a serious alcoholic with delirium tremens and pneumonia, there evolved, over a period of several days, a flaccid paralysis of all 4 limbs and an inability to chew, swallow, or speak (thus simulating occlusion of the basilar artery). Pupillary reflexes, movements of the eyes and lids, corneal reflexes, and facial sensation were spared. In some instances, however, conjugate eye movements are limited, and there may be nystagmus. With survival for several days, the tendon reflexes become


Neurology_Adams

Neurology_Adams. reflexes, and facial sensation were spared. In some instances, however, conjugate eye movements are limited, and there may be nystagmus. With survival for several days, the tendon reflexes become more active, followed by spasticity and extensor posturing of the limbs on painful stimulation. Some patients are left in a state of mutism and paralysis with relative intactness of sensation and comprehension (pseudocoma, or locked-in syndrome).


Neurology_Adams

Neurology_Adams. The capacity of CT and especially MRI to visualize the pontine lesion has greatly increased the frequency of premortem diagnoses. The MRI discloses a characteristic lesion of the pons in typical cases (Fig. 39-6), although this change may become evident only several days after the onset of symptoms. Brainstem auditory evoked responses also disclose the lesions that encroach upon the pontine tegmentum.


Neurology_Adams

Neurology_Adams. Variants of this syndrome are being encountered with increasing frequency. Two of our elderly patients, with confusion and stupor but without signs of corticospinal or pseudobulbar palsy, recovered; however, they were left with a severe dysarthria and cerebellar ataxia lasting many months. After 6 months, these patients’ nervous system function was essentially restored to normal. In reference to the pathogenesis of this lesion, originally both patients had serum Na levels of 99 mEq/L, but information about the rate of correction of serum Na was not available. Another of our patients developed a typical locked-in syndrome after the rapid correction of a serum sodium of 104 mEq/L. He had large symmetrical lesions of the frontal cortex and underlying white matter but no pontine lesion.


Neurology_Adams

Neurology_Adams. Brainstem infarction caused by basilar artery occlusion may be simulated by pontine myelinolysis. Sudden onset or step-like progression of the clinical state, asymmetry of long tract signs, and more extensive involvement of tegmental structures of the pons as well as the midbrain and thalamus are the distinguishing characteristics of vertebrobasilar thrombosis or embolism. On MRI studies, an evolving infarction shows signal changes on diffusion-weighted imaging, while the primary finding in osmotic demyelination is abnormal hyperintensity on T2-weighted images without associated restricted diffusion. Massive pontine demyelination in acute or chronic relapsing multiple sclerosis rarely produces a pure pontine syndrome. The clinical features and context provide the clues to correct diagnosis.


Neurology_Adams

Neurology_Adams. As mentioned in the section on hyponatremia, a rapid rise in serum osmolality to normal or higher-than-normal levels is an almost obligate antecedent of this process. One encounters this most commonly in the rapid correction of hyponatremia. In cases related to the correction of hyponatremia, the initial serum sodium concentration is less than 130 mEq/L and usually much lower; this was the case in all the patients reported by Burcar and colleagues and by Karp and Laureno. Laureno (1983) demonstrated the importance of serum sodium in the pathogenesis of this disease experimentally. Dogs made severely hyponatremic (100 to 115 mEq/L) had the electrolyte disorder corrected rapidly by infusion of hypertonic (3 percent) saline; this led to spastic quadriparesis and pontine and extrapontine lesions were found at autopsy, indistinguishable in their distribution and histologic features from those of the human disease. Hyponatremia alone or slowly corrected hyponatremia (<15 mEq/dL in the


Neurology_Adams

Neurology_Adams. lesions were found at autopsy, indistinguishable in their distribution and histologic features from those of the human disease. Hyponatremia alone or slowly corrected hyponatremia (<15 mEq/dL in the initial 24 h) did not produce the disease.


Neurology_Adams

Neurology_Adams. McKee and colleagues adduced that in burn patients, extreme serum hyperosmolality was the important factor in the pathogenesis of demyelination. They found the characteristic pontine and extrapontine lesions in 10 of 139 severely burned patients who were examined after death. Each of their patients with CPM had suffered a prolonged, nonterminal episode of severe serum hyperosmolality, which coincided temporally with the onset of the lesion, as judged by its histologic features. Hyponatremia was not prominent and no other independent features could explain the changes. These observations suggest that rapidly rising osmolarity may be a cause of the osmotic demyelination syndromes. The pathogenesis is not known but all one can say is that specific myelinated regions of the brain, most often but not exclusively the center of the base of the pons, have a susceptibility to rapid increase in serum osmolality.


Neurology_Adams

Neurology_Adams. Karp and Laureno, on the basis of their experience and that of Sterns and colleagues, have suggested that to avoid CPM the hyponatremia be corrected by no more than 10 mEq/L in the initial 24 h and by no more than about 21 mEq/L in the initial 48 h. Current recommendations are even more conservative—that the rate of correction of hyponatremia should not exceed 6 to 8 mEq/L over any 24-hour period.


Neurology_Adams

Neurology_Adams. These syndromes are usually of mixed type; that is, they include a number of basal ganglionic and cerebellar symptoms in various combinations. They emerge as part of acquired chronic hepatocerebral degeneration or chronic hypoparathyroidism or as sequels to kernicterus, hypoxic, or hypoglycemic encephalopathy. The basal ganglionic–cerebellar symptoms that result from severe anoxia and hypoglycemia were described in the preceding section and in Chaps. 4 and 5. Kernicterus and calcification of the basal ganglia and cerebellum are considered in Chap. 36 and further on in this chapter. Acquired hypoparathyroidism may also lead to calcification of the basal ganglia and an extrapyramidal disorder. Choreiform movements are also observed in patients with hyperosmolar coma and with severe hyperthyroidism, ascribed by Weiner and Klawans to a disturbance of dopamine metabolism.


Neurology_Adams

Neurology_Adams. Patients who survive an episode or several episodes of hepatic coma are sometimes left with residual neurologic abnormalities such as tremor of the head or arms, asterixis, grimacing, choreic movements and twitching of the limbs, dysarthria, ataxia of gait, or impairment of intellectual function. These symptoms may worsen with repeated attacks of stupor and coma. In few patients with chronic liver disease, permanent neurologic abnormalities become manifest in the absence of discrete episodes of hepatic coma. Patients deteriorate neurologically over a period of months or years. Examination of their brains discloses foci of destruction of nerve cells and other parenchymal elements in addition to a widespread transformation of astrocytes, changes very much similar to those of Wilson disease.


Neurology_Adams

Neurology_Adams. Probably the first to describe this acquired type of hepatocerebral degeneration was van Woerkom, whose report appeared only 2 years after Wilson’s original description of the familial form. A full account of the cases reported since that time as well as the extensive experience of our colleagues with this disorder is contained in the article by Victor, Adams and Cole.


Neurology_Adams

Neurology_Adams. The first symptom may be a tremor of the outstretched arms, fleeting arrhythmic twitches of the face and limbs (resembling either myoclonus or chorea), or a mild unsteadiness of gait with action tremor. As the condition evolves over months or years, a characteristic dysarthria, ataxia, wide-based, unsteady gait, and choreoathetosis, mainly of the face, neck, and shoulders, are joined in a syndrome. Mental function is slowly altered, taking the form of a dementia with a seeming lack of concern about the illness. A coarse, rhythmic tremor of the arms appearing with certain sustained postures, corticospinal tract signs (“hepatic paraplegia”), and diffuse EEG abnormalities complete the clinical picture. Other less-frequent signs are rigidity, grasp reflexes, tremor in repose, nystagmus, asterixis, and action or intention myoclonus. In essence, each of the neurologic abnormalities observed in patients with acute hepatic encephalopathy are also part of chronic hepatocerebral degeneration,


Neurology_Adams

Neurology_Adams. and action or intention myoclonus. In essence, each of the neurologic abnormalities observed in patients with acute hepatic encephalopathy are also part of chronic hepatocerebral degeneration, the only difference being that the abnormalities are evanescent in the former and irreversible and progressive in the latter.


Neurology_Adams

Neurology_Adams. As a rule, all measurable hepatic functions are altered but the chronic neurologic disorder correlates best with an elevation of serum ammonia (usually >200 mg/dL). Unlike Wilson disease, where the cirrhosis usually remains occult for a long time, there is no question about its presence in the acquired syndrome; jaundice, ascites, and esophageal varices are manifest in most of the acquired cases. Wilson disease, which enters into the differential diagnosis, is usually not difficult to differentiate on clinical grounds, although the distinction in some cases requires the critical evidence of familial occurrence, Kayser-Fleischer rings (never found in the acquired type), and certain biochemical abnormalities (diminished serum ceruloplasmin, elevated serum copper, and elevated urinary copper excretion, discussed in Chap. 39).


Neurology_Adams

Neurology_Adams. The cerebral lesions are localized more regularly in the cortex than is the case in Wilson disease. In some specimens an irregular gray line of necrosis or gliosis can be observed throughout both hemispheres and the lenticular nuclei may be shrunken and discolored. These lesions resemble hypoxic ones and may be concentrated in the vascular border zones but they tend to spare the hippocampus, globus pallidus, and deep folia of the cerebellar cortex, the sites of predilection in anoxic encephalopathy. Microscopically, a widespread hyperplasia of protoplasmic astrocytes is visible in the deep layers of the cerebral cortex and in the cerebellar cortex as well as in thalamic and lenticular nuclei and other nuclear structures of the brainstem. In the necrotic zones, the myelinated fibers and nerve cells are destroyed, with marginal fibrous gliosis; at the corticomedullary junction, in the striatum (particularly in the superior pole of the putamen) and in the cerebellar white matter,


Neurology_Adams

Neurology_Adams. and nerve cells are destroyed, with marginal fibrous gliosis; at the corticomedullary junction, in the striatum (particularly in the superior pole of the putamen) and in the cerebellar white matter, microcavitation may be prominent. Protoplasmic astrocytic nuclei contain PAS-positive glycogen granules. Some nerve cells appear swollen and chromatolyzed, taking the form of the Opalski cells usually associated with Wilson disease. The similarity of the lesions in the familial and acquired forms of hepatocerebral disease is striking.


Neurology_Adams

Neurology_Adams. Pathogenesis It is evident that a close relationship exists between the acute, transient form of hepatic encephalopathy and the chronic, largely irreversible hepatocerebral syndrome; frequently one blends imperceptibly into the other. The feature that ties these entities is the existence of portal–systemic shunting of blood. As noted above, this relationship is reflected in the pathologic findings as well. It appears that the parenchymal damage in the chronic disease simply represents the most severe degree of a pathologic process that in its mildest form is reflected in an astrocytic hyperplasia alone. Reducing the serum ammonia by the measures that are effective in acute hepatic encephalopathy will cause a recession of many of the chronic neurologic abnormalities—not completely, but to an extent that permits the patient to function better.


Neurology_Adams

Neurology_Adams. This condition and pseudohypoparathyroidism were mentioned in relation to the hereditary metabolic disorders in Chap. 36. In the past, the usual cause was surgical removal of the parathyroid glands during subtotal thyroidectomy, although there continue to be idiopathic cases. With refinements in surgical technique and the use of radiation and drug therapy for thyroid disease, the number of surgically created cases has declined in proportion to nonsurgical ones. The condition in children may occur in pure form, presumably as an agenesis of the parathyroid glands, with unmeasurable levels of parathyroid hormone in the blood, or as part of the DiGeorge syndrome of agenesis of the thymus and parathyroid glands, organs that are embryologically derived from the third and fourth branchial clefts. Hypoparathyroidism is also part of a familial disorder in which a deficiency of thyroid, ovarian, and adrenal function, pernicious anemia, and other defects are combined, based presumably on


Neurology_Adams

Neurology_Adams. clefts. Hypoparathyroidism is also part of a familial disorder in which a deficiency of thyroid, ovarian, and adrenal function, pernicious anemia, and other defects are combined, based presumably on autoimmune mechanisms. Other causes are intestinal malabsorption, pancreatic insufficiency, and vitamin D deficiency. In all instances the low levels of parathormone and normal responses to injected hormone permit the recognition of a primary defect of the parathyroid glands and distinguish it from all other conditions in which there is hypocalcemia and hyperphosphatemia.


Neurology_Adams

Neurology_Adams. The clinical manifestations, mainly attributable to the effects of hypocalcemia, are tetany, paresthesias, muscle cramps, laryngeal spasm, and convulsions. Children with this disease may be irritable and show behavioral changes. In adults with chronic hypocalcemia, calcium deposits occur in the basal ganglia, dentate nuclei, and cerebellar cortex. In such patients we have observed unilateral tremor, a restless choreoathetotic hand, bilateral rigidity, slowness of movement and flexed posture resembling Parkinson disease, and ataxia of the limbs and gait—in various combinations. Interestingly, the multiple skeletal and developmental abnormalities that characterize both pseudohypoparathyroidism (a failure of sensitivity to the hormone) and pseudopseudohypoparathyroidism (short stature, round face, short neck, stocky body build, shortening of metacarpal and metatarsal bones and phalanges from premature epiphyseal closure) are rarely seen in pure hypoparathyroidism.


Neurology_Adams

Neurology_Adams. A similar deposition of iron and calcium in the walls of small blood vessels of the lenticular and dentate nuclei, and to a lesser extent in other parts of the brain, is a common finding in normal older individuals (Fahr disease). It also occurs in animals. Occasionally, it reaches a degree of severity that destroys striatal or dentate neurons. In such cases, CT will reveal the deposits (see Fig. 36-8), but the cause of the deposits is unknown. Apparently some protein in the capillary walls has an avidity for both calcium and iron. The association of myxedema and cerebellar ataxia has been mentioned sporadically in medical writings since the latter part of the nineteenth century. Jellinek and Kelly described 6 such cases; all showed gait ataxia; in addition, some degree of ataxia of the arms and dysarthria were present in 4, and nystagmus in 2. Cremer and coworkers reported a similar clinical experience based on a study of 24 patients with either primary or secondary hypothyroidism.


Neurology_Adams

Neurology_Adams. There are only a few reports of the pathologic changes. The myxedematous patient described by Price and Netsky had also been an alcoholic, and the clinical signs (ataxia of gait and of the legs) and pathologic changes (loss of Purkinje cells and gliosis of the molecular layer, most pronounced in the vermis) could be distinguished from those caused by alcoholism and malnutrition. Scattered throughout the nervous system of their case were unusual glycogen-containing bodies, similar but not identical to corpora amylacea. These structures, designated myxedema bodies by Price and Netsky, were also observed in the cerebellar white matter of a second case of myxedema; there were no other neuropathologic changes, however, and this patient had shown no ataxia during life. It is difficult to know whether these peculiar bodies have anything to do with myxedema. If they do, it should be possible to demonstrate them in more than 2 cases. Our colleagues did not see them in one carefully studied


Neurology_Adams

Neurology_Adams. whether these peculiar bodies have anything to do with myxedema. If they do, it should be possible to demonstrate them in more than 2 cases. Our colleagues did not see them in one carefully studied case of myxedema, nor have they been described by others. Serum creatine kinase (CK) is also slightly elevated in hypothyroidism, presumably because of its slowed metabolism. Thyroid medication corrects the defect in motor coordination and normalizes the CK, raising the possibility that this is the result of a subcellular mechanism.


Neurology_Adams

Neurology_Adams. Table 5-3 summarizes the various causes of cerebellar ataxia, including the metabolic ones. Notable metabolic disorders, some heritable, in which ataxia may be a leading manifestation include GM2 gangliosidosis, possibly sprue (discussed below), and a large number of neonatal and infantile aminoacidopathies. Effects of Hyperthermia on the Cerebellum The damaging effects of hyperthermia, like those of anoxia, involve the brain diffusely. In the case of hyperthermia, however, the changes are disproportionately severe in the cerebellum. The acute manifestations of profound hyperthermia are coma and convulsions, frequently complicated by shock and renal failure. Patients who survive the initial stage of the illness frequently show signs of widespread cerebral affection, such as confusion and pseudobulbar and spastic paralysis. These abnormalities tend to resolve gradually, leaving the patient with a more or less pure disorder of cerebellar function.


Neurology_Adams

Neurology_Adams. The most extensive account of the effects of hyperthermia is that of Malamud and colleagues. These authors studied 125 fatal cases of heat stroke but their observations are probably applicable to hyperthermia of other types. In patients who survived less than 24 h, the changes consisted mainly of a loss of some of the Purkinje cells and swelling, pyknosis, and disintegration of those that remained. In cases surviving beyond 24 h, there was almost complete degeneration of the Purkinje cells, with gliosis throughout the cerebellar cortex as well as degeneration of the dentate nuclei. The changes in the cerebellar cortex were equally pronounced in the hemispheres and vermis. The unanswered question is whether high temperature alone is an adequate cause or whether it must be combined with hypoxia and ischemia. It is of interest that this syndrome is not seen in patients with infective fevers, malignant hyperthermia, or the malignant neuroleptic syndrome—either the neuropathologic changes


Neurology_Adams

Neurology_Adams. and ischemia. It is of interest that this syndrome is not seen in patients with infective fevers, malignant hyperthermia, or the malignant neuroleptic syndrome—either the neuropathologic changes or the clinical cerebellar syndrome in survivors.


Neurology_Adams

Neurology_Adams. Cerebellar Syndromes Associated With Celiac Disease (Sprue, Gluten Sensitive Enteropathy) Most often, the neurologic association with this disease has been a peripheral neuropathy, as described in Chap. 43. In addition, a progressive cerebellar ataxia of gait and limbs, sometimes with polymyoclonus in association with a gluten-sensitive enteropathy, has been the subject of several reports. The underlying cause of the enteropathy is an intestinal allergy to gluten in wheat that produces a villous atrophy of the intestinal mucosa. Between 0.5 and 1 percent of the white population are affected with the intestinal disorder. The classic features are diarrhea and malabsorption but many individuals are asymptomatic (see also Chap. 40).


Neurology_Adams

Neurology_Adams. The neurologic disorder may appear several years after onset of the enteropathy and, in addition to ataxia, usually includes signs of peripheral neuropathy and rarely, myelopathy or encephalopathy (dementia) or psychiatric symptoms (Hallert and Astrom; Hallert and Deerefeldt). A rare spinocerebellar syndrome was described by Cooke and Smith. According to Finelli and colleagues, neurologic abnormalities occur in approximately 10 percent of cases of adult celiac sprue. This subject was reviewed by Bhatia and colleagues and extensively by Hadjivassiliou and colleagues (1998, 2002). The latter authors emphasize the frequent occurrence of ataxia in patients with gluten sensitivity and, more specifically, antibodies to transglutaminase and endomysium, but, curiously, often without overt signs of bowel disease. There is also an association of sprue in more than 90 percent of patients with the HLA DQ2 and DQ8 genotypes. The few cases that have come to autopsy have shown severe cerebellar


Neurology_Adams

Neurology_Adams. of bowel disease. There is also an association of sprue in more than 90 percent of patients with the HLA DQ2 and DQ8 genotypes. The few cases that have come to autopsy have shown severe cerebellar atrophy, a finding that may also be disclosed by MRI. Hadjivassiliou and colleagues (1998) observed lymphocytic infiltration and perivascular cuffing in the cerebellar cortex and peripheral nerves in 1 autopsied case but not in another, changes that they took to represent immunologic injury to these parts.


Neurology_Adams

Neurology_Adams. Despite these associations, some authors have been skeptical of a “gluten ataxia” (see the editorial by Cross and Golumbek and the contrary case for a valid connection by Hadjivassiliou et al [2002]). Reports of improvement in the ataxia following the institution of a gluten-free diet are conflicting. The situation is further complicated by the finding that antigliadin antibodies (which are not autoantibodies but are directed against gluten, the offending agent), while not specific for celiac disease, do correspond to the presence of neurologic manifestations (ataxia and neuropathy); however, the more specific antiendomysium and antitransglutaminase autoantibody markers of sprue have little apparent relation to the presence of neurologic disease. Even more confusing is the claim that half of these patients will have one or another antibody but no clinical enteropathy, making it necessary to perform a small-bowel biopsy to detect villous atrophy.


Neurology_Adams

Neurology_Adams. A gluten-free diet is necessary, not only to reduce the enteropathy, if present, but also to reduce the chances of the later development of a bowel lymphoma. The medical issues relating to celiac disease and the use of antibody tests and bowel biopsy are reviewed by Farrell and Kelly. We have sought evidence by antibody testing and bowel biopsy of sprue in numerous patients with an ataxia of obscure origin and have only rarely found it. Nevertheless, the evidence presented in the writings of several authors, particularly Hadjivassiliou, suggest that sprue may underlie some cases of subacute ataxia in adults. Paraneoplastic cerebellar degeneration and Creutzfeldt-Jakob disease should always be considered in the differential diagnosis of a case of subacute cerebellar ataxia. Vitamin E deficiency may induce a similar syndrome with features of spinocerebellar dysfunction.


Neurology_Adams

Neurology_Adams. Jejunoileal bypass operations, in addition to causing a chronic arthropathy, neuropathy, and vasculitic skin lesions, may give rise to an episodic confusion and cerebellar ataxia associated with a lactic acidosis and abnormalities of pyruvate metabolism. Overfeeding and fasting are provocative factors (Dahlquist et al).


Neurology_Adams

Neurology_Adams. The point has been made that milder forms of metabolic diseases that cause episodic stupor and coma, if persistent, may have a protracted course and are then difficult to distinguish from the dementias (Chap. 20). Examples are associated with chronic hepatic encephalopathy and the syndromes of episodic hypoglycemia, chronic hypercalcemia (in multiple myeloma, metastatic cancer, and sarcoidosis), hyponatremia, and hypernatremia. Unlike the common types of dementia described in Chap. 20, the acquired metabolic diseases are nearly always accompanied by a degree of drowsiness and inattentiveness—attributes that usually allow an encephalopathic confusional state to be distinguished from a dementia. The presence of asterixis is also an aid. If the onset of the illness is abrupt rather than gradual and of brief duration, and if therapy reverses the condition, restoring full mental clarity, the conclusion is justified that one is dealing with a confusional state, but at any one time in the


Neurology_Adams

Neurology_Adams. and of brief duration, and if therapy reverses the condition, restoring full mental clarity, the conclusion is justified that one is dealing with a confusional state, but at any one time in the active phase of the disease, the clinical state may resemble dementia.


Neurology_Adams

Neurology_Adams. In general hospitals, an episodic confusional state lasting days and weeks in the course of a medical illness or following an operation should always raise the suspicion of one of the aforementioned metabolic derangements (or an adverse effect of a drug). Usually, however, if these causes can be excluded, one falls back on a rather unsatisfactory interpretation—that a combination of drugs, fever, toxemia, and unspecifiable metabolic disorders is responsible. The “septic encephalopathy” described earlier in this chapter conforms to this ambiguous notion. In the endocrine encephalopathies described below, the clinical phenomena may take the form of a delirium. Confusional states may be combined with agitation, hallucinations, delusions, anxiety, and depression, and the time span of the illness may be in terms of weeks and months rather than days. Certain aspects of the endocrine psychoses are discussed further on.


Neurology_Adams

Neurology_Adams. Derangements of mental function that follow administration of adrenocorticotropic hormone (ACTH) and of corticosteroids have become the prototypes of iatrogenic psychoses. The same disturbances of mental function may accompany Cushing disease (see “Corticosteroid and Adrenocorticotropic Hormone Psychosis” in Chap. 49). Experience with this neuropsychiatric condition came originally from observations of patients receiving ACTH and later from those receiving prednisone for a variety of neurologic and medical diseases. With low doses there is usually no psychic effect other than a sense of well-being and decreased fatigability. At higher doses (equivalent to 60 to 100 mg/d of prednisone), approximately 10 to 15 percent of patients become overly active, emotionally labile, and unable to sleep. Unless the dose is promptly reduced, a progressive shift in mood follows, usually toward euphoria and hypomania, but sometimes toward depression and then inattentiveness, distractibility, and mild


Neurology_Adams

Neurology_Adams. Unless the dose is promptly reduced, a progressive shift in mood follows, usually toward euphoria and hypomania, but sometimes toward depression and then inattentiveness, distractibility, and mild confusion. The EEG becomes less-well modulated and slower frequencies appear. A minority of patients experience frank hallucinations and delusions, giving the illness a truly psychotic stamp and raising the suspicion of schizophrenia or bipolar disease. In nearly all instances, there is a mixture of confusion and mood change, distinguishing the state from other mundane metabolic encephalopathies. Withdrawal of medication relieves the symptoms but full recovery may take several days to a few weeks, at which time, as with all confusional states and deliria, the patient has only a fragmentary recollection of events that occurred during the illness.


Neurology_Adams

Neurology_Adams. The neurologic basis of this condition is poorly understood. Its attribution to premorbid personality traits or a disposition to psychiatric illness is unconvincing. Critical studies of cellular or subcellular metabolism and morphologic changes are lacking. “Cerebral atrophy” (ventricular enlargement and sulcal widening) has been shown radiologically in patients with Cushing disease and after a prolonged period of corticosteroid therapy, but the basis of this change also is unclear (Momose et al). In most cases of brain shrinkage, withdrawal of steroids has led to a reduction in ventricular size, as documented on sequential imaging studies.


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Neurology_Adams. In patients with Cushing disease because of adrenal or basophilic pituitary tumors, mental changes suggestive of dementia and enlarged ventricles are unusual, especially by comparison to the incidence of these changes with exogenous corticosteroids. Here again, there is a peculiar combination of mood changes and impaired cognitive function. A frank psychosis may occur. This condition is described more completely in Chap. 49 and the attendant proximal myopathy, in Chap. 45.


Neurology_Adams

Neurology_Adams. Allusions to psychosis in thyrotoxic patients are frequent in the medical literature. Mental confusion, seizures, manic or depressive attacks, and delusions occur singly or in combination. Action tremor is almost universal, and chorea occurs occasionally in various combinations with proximal muscular weakness. In descriptions of abnormal movements, it is often not clear whether it was chorea, tremor, myoclonus, or just fidgetiness that was observed. Treatment of the hyperthyroidism gradually restores the mental state to normal, leaving one with no explanation of what had happened to the CNS. The separate and special associations of hyperthyroidism with periodic paralysis and myasthenia are discussed in later chapters.


Neurology_Adams

Neurology_Adams. Thyroid crisis or “storm” refers to a fulminant increase in the symptoms and signs of thyrotoxicosis—extreme restlessness, tachycardia, fever, vomiting, and diarrhea—leading to delirium or coma. In the past, this was a not uncommon postoperative event in patients poorly prepared for thyroid surgery. Now it is seen mainly in patients with inadequately treated or untreated thyrotoxicosis complicated by serious medical or surgical illness.


Neurology_Adams

Neurology_Adams. Brain and associates described an encephalopathy consisting of confusion, altered consciousness, and prominent myoclonus in patients with Hashimoto disease. The details were further elaborated by Shaw and colleagues and by Chong and associates. Some cases have had a relapsing course over months or years. It is important to note that most have had normal thyroid function. There are in these cases, however, high titers of several antithyroid antibodies, particularly antibodies against thyroid peroxidase and thyroglobulin; some affected individuals have more than one such antibody. Ferracci and colleagues found evidence of the production of these antibodies in the nervous system and of their presence in spinal fluid. One must be cautious, however, in interpreting the presence of antithyroid antibodies in the blood, as they are detected in many people without an encephalopathy, particularly older women, and in two-thirds of patients with Graves disease.


Neurology_Adams

Neurology_Adams. The most commonly observed syndrome is of confusion or stupor accompanied by multifocal myoclonus, but seizures—including myoclonic and rarely, nonconvulsive status epilepticus, may occur as well. Hemiparesis, ataxia, psychosis, and unusual tremors, including those of the palate, have been reported in individual cases as in the series reported by Castillo and colleagues; they found tremor, transient aphasia, myoclonus, ataxia and seizures to be present in that order of frequency. Many had liver function abnormalities and one-fifth showed inflammatory changes in the CSF. Some of the reports included children.