Neurologic manifestations of diabetic comas: Correlation with biochemical alterations in the brain

Coma and other neurologic abnormalities are present in patients with either diabetic ketoacidosis (DKA) or nonketotic coma (NKC), and the cause of such phenomena are not known. Patients with NKC also manifest seizures and focal neurologic changes. Treatment of diabetic coma with insulin may induce cerebral edema by as yet undefined mechanism(s). In patients with DKA, cerebral oxygen utilization is impaired, and there is hyperviscosity of the blood. A substantial part of the brain's energy source is derived from ketones, which in themselves can depress sensorium. Extracellular hyperosomolality is present, which may also contribute to the genesis of coma. In addition, most keto-acidotic patients have associated medical conditions, which may further impair consciousness. Biochemical changes in the brains of animals with DKA include impairment of both phosphofructokinase activity and pyruvate oxidation, and accumulation of citrate. The net effect upon sensorium in ketoacidotic patients probably represents the interaction of most of the above factors and differs markedly among individuals. Patients with NKC manifest not only depression of sensorium, but also focal motor seizures, hemiparesis, and other neurologic changes, such as aphasia, hypereflexia, sensory defects, autonomic changes, and brainstem dysfunction. Most of the aforementioned changes revert to normal after correction of hyperosomolality. Gamma amino butyric acid, which has been shown to elevate the seizure threshold, is normal in brains of ketoacidotic animals, but may be low in nonketotic coma. Also, hyperosomolality per se may produce seizures. Cerebral edema may complicate the treatment of either DKA or NKC. The available experimental evidence suggests that many of the commonly held theories for the production of such brain swelling probably do not occur. There is no breakdown of the sodium pump, sorbitol or fructose do not accumulate in brain, and brain glucose is only about 25% of that in plasma. Cerebral edema is probably produced largely by a direct action of insulin on brain at a time when plasma glucose is approaching normal values. Cerebral edema can thus theoretically be avoided by stopping insulin when plasma glucose has been lowered to values approaching normal.     

Hyponatremia due to cerebral salt-wasting syndrome: Combined cerebral and distal tubular lesion

A 76-year-old white man was evaluated for a syndrome of hyponatremia, hypotension, and high urinary sodium excretion. There was evidence of inappropriate secretion of antidiuretic hormone and renal salt wasting in the presence of a normal glomerular filtration rate. He had a distal tubular acidification defect and unresponsiveness to standard doses of mineralocorticoids. The renin aldosterone axis was normal, as were thyroid and adrenal function. The patient could not dilute the urine, nor excrete a standard water load. Renal concentrating ability was normal, but there was no additional response to exogenous vasopressin. With modest salt restitution, the patient continued to lose large quantities of sodium in the urine, resulting in severe postural hypotension. Renal biopsy showed normal glomeruli with distinct degeneration of the distal tubules. There was no evidence of an acute inflammatory interstitial nephritis. The patient did not respond to therapeutic doses of mineralocorticoid (fludrocortisone), but treatment with water restriction, increased salt intake, and large doses of mineralocorticoids resulted In a normal serum sodium level and blood pressure. This case falls in the category of “cerebral salt wasting” syndrome. The cause was a combination of idiopathic secretion of antidiuretic hormone and distal tubular degeneration resulting in pseudohypoaldosteronism.     

Central nervous system manifestations of hyperparathyroidism

Prospective neurologic and psychologic studies were thus undertaken in 19 patients who were to undergo major neck operations either for parathyroidectomy (seven for primary hyperparathyroidism and six for secondary hyperparathyroidism) or other reasons (six control subjects). A complete physical and neurologic examination, laboratory tests (calcium, PTH), roentgenograms, a standard electroencephalogram and psychologic testing were carried out in patients before and three and a half months after neck operation.The preoperative electroencephalograms were abnormal in groups with both primary and secondary hyperparathyroidism. For the patients with primary hyperparathyroidism, the preoperative electroencephalogram revealed a percentage electroencephalographic power below 5 Hz (± SE) of 4.2 ± 2.2 per cent (normal = 2.4 ± 1.0 per cent), and the percentage of electroencephalographic frequencies below 7 Hz was 14.7 ± 3.2 per cent (normal = 6.0 ± 1.6 per cent). Postoperatively, however, there were significant (p < 0.01) decrements in these measurements to normal values. The percentage electroencephalographic power below 5 Hz was 1.5 ± 0.6 per cent, whereas the percentage of electroencephalographic frequencies below 7 Hz was 5.2 ± 1.1 per cent. In patients with secondary hyperparathyroidism, both the percentage electroencephalographic power below 5 Hz (9.7 ± 2.5 per cent, p < 0.01) and the percentage electroencephalographic frequencies below 7 Hz (22.2 ± 4.2 per cent, p < 0.01), were significantly higher than normal values. There were significant decrements in all the abnormal electroencephalographic values postoperatively. The percentage electroencephalographic power below 5 Hz decreased to 3.4 ± 2.4 per cent, and the percentage electroencephalographic frequencies below 7 Hz decreased to 17.4 ± 3.1 per cent. Electroencephalograms in control patients did not change.Patients with primary hyperparathyroidism showed no significant postoperative improvement in any of the psychologic parameters tested. By contrast, patients with secondary hyperparathyroidism showed improvement in several areas of testing after undergoing surgery when compared to control subjects.The brain calcium in four other patients with secondary hyperparathyroidism who died of miscellaneous causes was 38.3 ± 5.7 meq/kg dry wt, versus the normal value of 25.2 ± 0.7 meq/kg dry wt (p < 0.03).These data show that in patients with either primary or secondary hyperparathyroidism, the electroencephalogram is abnormal and shows significant improvement following parathyroidectomy. There is also improvement in several tests of intellectual function in patients with secondary hyperparathyroidism. Brain calcium content was significantly higher than normal in patients with secondary hyperparathyroidism.     

Evaluation of ethanol hypoglycemia in man: turnover studies with C-6 14C glucose

Glucose turnover (supply and utilization) was studied prior to and following the administration of alcohol to obese human subjects and human subjects of normal weight fasted for 3 days. Hypoglycemia was observed in all subjects. The rate of decrease in glucose concentration was significantly greater in subjects of normal weight than in obese subjects. It has been demonstrated that this difference is due to an average increase in the rate of glucose utilization in subjects of normal weight versus an average decline in the rate of glucose utilization in obese subjects during the production of hypoglycemia. The alterations observed in glucose supply and utilization were complex. Immediately following the initiation of the ethanol infusion, the rate of glucose utilization rose sharply in every individual. During this same period (0–35 min following alcohol) the rate of glucose supply rose in all but one individual in each group. In the subsequent portion of the period of production of hypoglycemia, glucose supply (presumably gluconeogenesis) was inhibited in every case. During this period, the rate of glucose utilization was observed to be greater than prealcohol rates in the individuals of normal weight, while in the obese individuals a decline was observed in the rate of glucose utilization compared to that observed prior to alcohol. In the final hours of these studies, a second steady state (constant low blood glucose concentration) was observed. The kinetics of glucose supply and utilization in the transition from progressive hypoglycemia to this terminal phase were again complex. All, but one individual, were found to have increased their rates of glucose supply over the inhibited rates observed during the production of hypoglycemia. At the same time, the rate of peripheral glucose utilization fell in every individual, ranging from a barely perceptible fall in the obese group to an average decrease of 40% in the individuals whose weight was normal. These studies indicate that there are factors other than inhibition of gluconeogenesis that contribute to the degree of hypoglycemia after alcohol in man fasted 72 hr.     

Effects of phosphate depletion on acid-base status in dogs.

Hyperchloremic acidosis may occur in patients with severe hypophosphatemia, including some with hyperparathyroidism. In experimental models of phosphate depletion, metabolic acidosis has not been a consistent feature. In some studies, arterial pH values have been normal, but have been associated with high rates of urinary bicarbonate loss. In other studies, metabolic acidosis has been observed associated with a decreased capacity for renal bicarbonate reabsorption. The present study was designed to examine the effects of both phosphate depletion upon systemic acid-base status in dogs and chronic hypophosphatemia upon renal bicarbonate reabsorption. Studies were performed upon three groups. All received a standard diet markedly diminished in phosphate content. Normal dogs (group I) received a dietary supplement of phosphate (31 mM/day). Group II dogs received no supplemental phosphate. Group III dogs were parathyroidectomized and also received a phosphate-deficient diet. Deprivation of dietary phosphate in groups II and III resulted in severe hypophosphatemia (Serum phosphate = 1.1 mg phosphorus/dl). Renal fractional phosphate reabsorption was increased significantly in both groups. Despite phosphate deprivation for up to 14 wk, arterial pH and bicarbonate values remained normal. Values for fasting urine pH and bicarbonate excretion were similar in the three groups. Renal bicarbonate conservation was normal in groups II and III as observed under fasting conditions. During bicarbonate infusion studies, patterns of bicarbonate reabsorption/glomerular filtration rate were obtained and maximal rates of renal bicarbonate reabsorption were assessed. To correct for possible differences ascribable to the effects of extracellular fluid volume expansion, the ratio of absolute bicarbonate/absolute sodium reabsorption was also examined. Over a wide range of plasma bicarbonate concentrations, no significant differences in this ratio were observed among the three groups. Maximal rates of renal bicarbonate reabsorption were similar in the three groups. The studies demonstrate that prolonged dietary phosphate deprivation in dogs, while resulting in severe hypophosphatemia, may be associated with the maintenance of normal plasma pH and bicarbonate values. Abnormal rates of urinary bicarbonate loss have not been observed. In the absence of metabolic acidosis, bicarbonate reabsorptive capacity and bicarbonate reabsorptive patterns are normal. The study suggests that other causes for the metabolic acidosis in severe phosphate depletion should be sought.     

Thiazide-induced hyponatremia associated with death or neurologic damage in outpatients

Seven elderly patients were encountered who had been taking thiazides or thiazide-like diuretics (hydrochlorothiazide, polythiazide or metolazone) for less than 16 days and who presented with severe symptomatic hyponatremia (serum SODIUM = 105 ± 6 meq/liter). In five patients, urine sodium + potassium was 156 meq/liter whereas that in serum was 108 meq/liter (P < 0.01). All patients had central nervous manifestations of hyponatremia (seizures, stupor, coma, extensor plantar response) and all but one were treated with 3 percent sodium chloride to raise the serum sodium level above 130 meq/liter within 44 hours. Three patients died, two had permanent paralysis, and two recovered. Other causes of the neurologic dysfunction were ruled out by negative lumbar punctures, brain scan and computerized axial tomography (CAT) scan. In all, serum creatinine was below 1.1 mg/dl.

The patients who recovered were studied. In two patients, the administration of oral metolazone (10 mg/day for two days) or hydrochlorothiazide (100 mg/day for two days) with ad libitum water intake resulted in decrements in serum sodium of 13 to 18 meq/liter in 36 hours. In both, serum sodium levels fell below 125 meq/liter with resultant symptoms. In one patient, the response to a standard oral water loading test was studied before and after 10 mg of metolazone administration. After metolazone therapy, the percent excretion of a standard oral water load in 4 hours fell from 65 percent to 15 percent, minimal urine osmolality, which had been 130 to 371 mosmol/kg, increased to 371 mosmol/kg, free water clearance fell from 2.25 to −0.25 ml/min and urine sodium excretion increased from 62 to 159 μeq/min. Plasma antidiuretic hormone (ADH) levels were undetectable before and after the administration of metolazone but rose after overnight dehydration. Thus, metolazone resulted in impaired ability to dilute the urine and excrete a water load, with 256 percent increase in urine sodium loss. Therefore, in a susceptible subgroup of outpatients, thiazides may rapidly induce severe hyponatremia with permanent neurologic damage or death.     

Transient cerebral ischemia: Pathophysiology

The clinical features of TIAs in the anterior and posterior cerebral circulations are fairly uniform and usually easily recognized. The pathogenesis of TIAs is varied, complex, and incompletely understood. The importance of TIAs rests on the fact that they may serve as dramatic warnings of an impending stroke. Depending on the type and cause of a TIA, medical therapy, alone or in combination with surgical intervention, can postpone or sometimes prevent permanent neurologic deficit. It is the task of the clinician first to determine which among many mechanisms—vascular, cardiac hematologic, or circulatory—is responsible for transient neurologic symptoms in an individual patient, and then to supply appropriate therapy as prophylaxis against a stroke.     

Sodium wasting, acidosis and hyperkalemia induced by methicillin interstitial nephritis. Evidence for selective distal tubular dysfunction.

A 61 year old male patient was studied who manifested dehydration, azotemia, acidosis and hyperkalemia six weeks after exposure to methicillin. Thyroid and adrenal glucocorticoid and mineralocorticoid function were normal. The dehydration was found to be caused by a profound sodium-losing nephropathy; urinary sodium ranged from 78 to 101 meq/day during a salt restricted diet. A distal renal tubular acidosis and a quantitively impaired ability to excrete potassium were also found. These defects were relatively unresponsive to mineralocorticoid or prednisone therapy. A renal biopsy specimen showed an interstitial nephritis which selectively affected distal tubules and was thought to be secondary to methicillin. The data suggest functional impairment specific for the distal tubule, but with only a modest decrease in the glomerular filtration rate.     

Mevalonate metabolism in pregnant rats

Mevalonate is converted to cholesterol by the sterol pathway or can be oxidized to CO₂ by the shunt pathway; the kidneys are the chief site of mevalonate metabolism in both pathways. Recently, a major sex difference in circulating mevalonate metabolism has been observed in rats and in humans; in rats, females oxidized mevalonate to CO₂ at twice the rate of the males, but males converted mevalonate to cholesterol to a greater extent than did females. Sex hormones are believed to mediate these sex differences in mevalonate metabolism. In rats and humans, the hypercholesterolemia associated with pregnancy begins in the second trimester and reaches a maximum at term. The present study was undertaken to determine if alterations in the metabolism of circulating mevalonate occur during pregnancy. In 12-day pregnant animals, the metabolism of circulating mevalonate by the shunt pathway was increased (116 nmole mevalonate converted to CO₂ versus 94.6 nmole in control animals), whereas in the 18-day pregnant animals the shunt pathway was decreased below control values (72.9 nmole). Associated with this decrease in circulating mevalonate metabolism by the shunt pathway in the 18-day pregnant animals was an increase in the synthesis of nonsaponifiable lipids in the liver (26.8 versus 21.5 nmole of mevalonate incorporated). These changes correlated with the period of maximal hypercholesterolemia in pregnant rats. The increase in circulating mevalonate metabolism by the shunt pathway in 12-day pregnant animals was accompanied by a decrease in total body nonsaponifiable lipid synthesis (259.3 nmole of mevalonate converted by controls versus 235.1 nmole by 12-day pregnant rats). Renal sterol synthesis from circulating mevalonate was unaffected by pregnancy. The fetuses and placentas of the 12-day and 18-day pregnant animals converted circulating mevalonate to nonsaponifiable lipids, primarily cholesterol, indicating that maternal circulating mevalonate serves as a source of cholesterol for the fetus and the placenta. This study demonstrates that the metabolism of circulating mevalonate is influenced by pregnancy and that circulating maternal mevalonate is a precursor of fetal and placental cholesterol.     

Beneficial hemodynamic effects of intravenous diazoxide in refractory congestive heart failure

Despite the growing popularity of vasodilator therapy for acute and chronic congestive heart failure (CHF), no single agent has been uniformly effective and well tolerated. Therefore, we investigated the acute hemodynamic response to diazoxide, a potent and long-acting arteriolar dilator, in nine patients with severe CHF refractory to conventional treatment and, in seven of nine, other vasodilators. Diazoxide was administered intravenously in successive 300 mg infusions, each over 10 minutes, until a satisfactory response in cardiac output occurred or a fall in arterial blood pressure or increase in heart rate was noted. The mean dose of diazoxide was 670 mg (range 450 to 900 mg). Systemic vascular resistance fell immediately, by a maximum of 44%. Arterial pressure was not changed significantly, but cardiac and stroke volume indices rose by 64% and 49%, respectively, from 2.0 ± 0.5 to 3.3 ± 0.6 L/min/m² and from 24 ± 10 to 36 ± 9 ml/m² (each p < 0.001). Pulmonary capillary wedge pressure declined more gradually, by a mean of 8 mm at 4 and 6 hours after drug infusion. This hemodynamic improvement was sustained for a mean of 9.7 hours (range 6 to 12 hours). Our findings indicate that intravenous diazoxide may be useful in the management of acute heart failure and that a trial of oral diazoxide in chronic normotensive CHF is warranted.     

Metabolic acidosis in the vitamin D-deficient chick

In vitamin D-deficient chicks raised from age 1 day on a vitamin D-deficient diet, hyperchloremic metabolic acidosis occurred at 3 wk and persisted. Within 24 hr of administration of vitamin D, the acidosis and hypocalcemia were attentuated; during the subsequent 72 hr the severity of the metabolic acidosis but not that of the hypocalcemia was further attenuated. That further attenuation occurred despite hypocalcemia of unchanging severity and presumed continuing secondary hyperparathyroidism suggests the possibility that vitamin D deficiency may be a requirement for the expression of metabolic acidosis. Since in vitro and in vivo studies suggest that subphysiologic values of media and blood pH, respectively, are attended by reduced production of 1,25-(OH)₂D₃, the most biologically active vitamin D metabolite known, the occurrence of acidosis in vitamin D deficiency may compound its metabolic consequences. The possible effects of acidosis must be considered in interpreting results of investigations of vitamin D metabolism in vitamin D-deficient chicks.     

Renal failure after major angiography

A recently reported 12 per cent incidence of renal failure following angiography prompted our prospective study to substantiate or repudiate this seemingly excessive rate. In 100 consecutive patients, there was no instance of renal failure following angiography. The results of our study indicate that when adequate hydration is maintained angiography does not pose a “significant hazard” of renal failure as previously reported, even in patients with underlying medical problems.     

Serum thyroxine, free T4, triiodothyronine, and reverse-T3 in diphenylhydantoin-treated patients.

In order to determine the effects of the administration of diphenylhydantoin (DPH) on various parameters of thyroid function, serum samples from 47 male adults receiving therapeutic doses of DPH and 45 euthyroid control subjects were analyzed for total thyroxine (T₄) and an index of free T₄ concentration, using both a competitive protein-binding assay (CPBA) and a solid-phase radioimmunoassay (RIA), total 3,5,3′-triiodothyronine (T₃), 3,3′,5′-triiodothyronine (reverse-T₃, rT₃), and TSH, each measured by specific RIA. Mean total T₄ by both methods was depressed in the DPH group to 0.78 of the control level. Free T₄ Index by RIA was decreased on the average in DPH-patients exactly in proportion to the depression in total T₄. By the CPBA, the difference between two groups in Free T₄ Index was less marked but still significant (DPH/controls = 0.86, p < 0.01). The concentrations of total T₃ were virtually identical in the DPH and the control groups. The average $\text{T}{}_3\text{T}{}_4$ ratio was significantly higher in the DPH patients than in the controls (0.0178 versus 0.0132, p < 0.001). Serum rT₃ was depressed by DPH-treatment in approximately the same proportion to the decrease in total T₄. None of the DPH-patients had an elevated serum TSH. The above findings are interpreted as indirect evidence in support of the view that DPH stimulates T₄ metabolism, particularly the conversion of T₄ to T₃. The normal level of free T₃ may help to maintain a euthyroid state in spite of the decrease in free T₄. The data also define the “euthyroid” ranges for total and free T₄ levels by these methods in patients receiving DPH.     

The mechanism of the acute hypoglycemic action of phenformin (DBI)

The mechanisms by which biguanide (phenformin) acutely brings about a reduction in blood glucose in diabetic subjects has been studied with the aid of C-6 ¹⁴C glucose. Six diabetic subjects were studied, each at three separate dose levels of phenformin. Two of these same subjects were studied with placebo. Consistent and increasingly pronounced effects of drug versus placebo were noted as the level of biguanide was increased. Biguanide consistently lowered hepatic glucose output while not significantly affecting the removal of glucose from the circulation. It was noted that glucogenesis from lactate was not significantly curtailed. However, a lack of stimulation in Cori Cycle activity in the presence of significant elevations of circulating lactate were taken as an indication of inhibition of glucogenesis from this substrate. On balance, it is concluded that the acute hypoglycemic action of this biguanide is mediated primarily through a restriction in the supply of glucose from the liver to the circulation. The data support the contention that these drugs inhibit hepati glucogenesis even though Cori Cycle activity may be increased and also suggest that a portion of the decrease in hepatic glucose supply may be the result of impaired glycogenolysis.     

Clinical studies with transdermal nitroglycerin

The short- and long-term effects of various Nitro-Dur formulations on performance and hemodynamics were studied in 15 men with stable angina pectoris who also had a positive treadmill exercise test. A treadmill exercise score (TES) was used that quantified the “ischemic” ST segment response to exercise. The score incorporated information that reflected the rapidity of evolution of ST segment depression during exercise and the time required for it to resolve after cessation of exercise. In early tests (n = 10) Nitro-Dur improved both the TES (by 31%: p < 0.0001) and the time required for 1 mm ST segment depression (by 33%: p < 0.0001). At all dosage levels, Nitro-Dur also decreased resting systolic blood pressure and increased resting heart rate. No dose-response patterns emerged. Changes in TES and time to ST segment depression were greater with sublingual nitroglycerin than they were with Nitro-Dur. In tests conducted after prolonged dosage (n = 5), the effects of Nitro-Dur on blood pressure and heart rate became attenuated at weeks 2 and 4, although cardiac responsiveness was preserved, as reflected in the increased time required before the occurrence of 1 mm ST segment depression. The latter effect was also observed with sublingual nitroglycerin. The clinical relevance of these data to the design of individual patient therapy is discussed.     

Production of triiodothyronine in normal human subjects and in patients with hyperthyroism. Contribution of intrathyroid iodine analysis

Alexander Gutman was a pioneer in measuring total iodine and L-thyroxine (T₄) concentrations within the thyroid gland nearly 50 years ago. On this foundation, new analytical technics developed in the intervening years greatly expanded knowledge of intrathyroid hormone content. This review examines how the latter has contributed to the understanding of the physiology and physiopathology of specific problems currently of great Interest in thyroid research; namely, the source of circulating triiodothyronine (T₃) in normal man and the course of a newly described clinical entity, T₃-toxicosis.The recent conclusive demonstration of the peripheral conversion of T₄ to T₃ in man raises the question of the proportion of total T₃ production normally derived from this pathway, as opposed to direct thyroid secretion. Direct analyses of T₄ to T₃ ratios in human thyroid tissue suggest that relatively little T₃ is derived directly from the thyroid; however, the inhomogeneity of intrathyroidal iodine pools, and the possibility that T₄ may be converted to T₃ within the thyroid, make this approach of limited value. The problem will be settled only by careful kinetic analyses making possible a comparison between the total T₃ production rate and that derived from peripheral T₄ deiodination.T₃ toxicosis is a recently described entity in which hyperthyroidism is associated with an increased serum T₃ concentration, together with a normal or decreased concentration of T₄. In the usual form of thyrotoxicosis, in which both T₄ and T₃ levels are elevated, the thyroid also secretes disproportionately large quantities of T₃ relative to T₄. Since there is evidence in animals and man that iodine deficiency favors synthesis and secretion of T₃ relative to T₄, the relative-hypersecretion of T₃ in both varieties of thyrotoxicosis may reflect a relative intrathyroid iodine deficiency. That this possibility is more than speculative is suggested by Gutman's early finding of a decrease in the total iodine and T₄ content of thyrotoxic glands. The mechanism whereby intrathyroid iodine depletion may occur in the thyrotoxic gland remains obscure, however.