Role of impaired lower-limb venous innervation in the pathogenesis of the chronic fatigue syndrome.

BACKGROUND: In patients with acute orthostatic hypotension, there is excessive pooling of blood in the legs, which may result from the strikingly subnormal compliance that is demonstrable in the pedal veins during norepinephrine infusion. The common occurrence of delayed orthostatic hypotension and/or tachycardia in the chronic fatigue syndrome (CFS) led to the present studies of foot vein compliance in CFS patients with a linear variable differential transformer. METHODS: Seven patients with CFS were compared with 7 age- and gender matched healthy control subjects in their blood pressure, heart-rate, and plasma norepinephrine responses to prolonged standing and in measurements of their foot vein contractile responses to intravenous norepinephrine infusions with the linear variable differential transformer. RESULTS: Excessive, delayed (usually after 10 min) orthostatic reductions in systolic and diastolic blood pressure (P < 0.01) and inconsistently excessive increases in heart rate were found in the CFS patients, in whom venous compliance in response to infused norepinephrine was significantly reduced (P < 0.05). CONCLUSIONS: In these patients with CFS, delayed orthostatic hypotension was clearly demonstrable, and, as in previously reported patients with orthostatic hypotension of acute onset, this was associated with reduced pedal vein compliance during norepinephrine infusion, implying impaired sympathetic innervation of foot veins. The rapid symptomatic improvement demonstrated in previous studies of CFS patients during correction of orthostatic venous pooling by inflation of military antishock trousers (MAST) to 35 mm Hg may suggest that excessive lower body venous pooling, perhaps by reducing cerebral perfusion, is involved in the orthostatic component of fatigue in these patients.

The roles of orthostatic hypotension, orthostatic tachycardia, and subnormal erythrocyte volume in the pathogenesis of the chronic fatigue syndrome.

BACKGROUND: Orthostatic hypotension during upright tilt is an important physical disorder in patients with chronic fatigue syndrome. We have tested its occurrence during prolonged standing, whether it is correctable, and whether reduced circulating erythrocyte volume is present. METHODS: Fifteen patients were randomly selected from a large population of patients with chronic fatigue syndrome, studied, and observed for several years (by DSB). Blood pressure (BP) and heart rate (HR) measured with Dinamap every minute for 30 minutes supine and 60 minutes standing were compared with these findings in 15 healthy age- and gender-matched control subjects and later during lower body compression with military antishock trousers (MAST). Plasma catecholamines and circulating erythrocyte and plasma volumes were also measured by isotopic dilution methods. RESULTS: Abnormal findings in the patients included excessive orthostatic reductions in systolic (P < 0.001) and diastolic BP (P < 0.001) and excessive orthostatic tachycardia (P < 0.01), together with presyncopal symptoms in 11 of the 15 patients and in none of the control subjects after standing for 60 min. Lower body compression with the MAST restored all orthostatic measurements to normal and overcame presyncopal symptoms within 10 min. Circulating erythrocyte but not plasma volumes were subnormal in the 12 women (P < 0.01) and plasma norepinephrine concentration rose excessively after standing for 10 min. CONCLUSION: Delayed orthostatic hypotension and/or tachycardia caused by excessive gravitational venous pooling, which is correctable with external lower-body compression, together with subnormal circulating erythrocyte volume, are very frequent, although not invariably demonstrable, findings in moderate to severe chronic fatigue syndrome. When present, they may be involved in its pathogenesis.

Orthostatic intolerance. A historical introduction to the pathophysiological mechanisms.

Several of the pathophysiological mechanisms resulting in orthostatic intolerance (ie, tachycardia) have been recognized individually over the course of the past 100 years or more. More recent definitions of the normal ranges of orthostatic blood pressure and heart rate changes have facilitated the recognition of pathogenetic disorders that are probably shared in various proportions between orthostatic intolerance and various types of orthostatic hypotension. These include autonomic dysfunction of (1) the leg veins almost invariably causing excessive gravitational blood pooling, usually associated with (2) hypovolemia of circulating erythrocytes and plasma that is probably attributable to impaired autonomic stimulation of erythropoietin production, renin release, and (less consistently) aldosterone secretion. Improved understanding of these apparent results of lower body dysautonomia should facilitate more effective therapy in the future.

A longitudinal study of blood pressure in relation to performance on the Wechsler Adult Intelligence Scale.

A growth curve analysis was used to examine estimated longitudinal decline (over 19 years) on the Wechsler Adult Intelligence Scale (WAIS; D. Wechsler, 1955) in relation to arterial hypertension and blood pressure (BP) for 55 men and 85 women (40 to 70 years old) who were free from overt major coexisting diseases. BP was associated with longitudinal decline for Visualization-Performance (VP) ability and Speed. Hypertension was a weaker predictor of VP and was unrelated to Speed. Age effects on VP were overestimated when averaged BP level, particularly systolic BP, was not controlled statistically. It was concluded that initial BP level and hypertension predict age-related longitudinal decline in specific major abilities assessed by the WAIS but that BP averaged over examinations is a stronger predictor.

Autosomal dominant orthostatic hypotensive disorder maps to chromosome 18q.

Familial orthostatic hypotensive disorder is characterized by light-headedness on standing, which may worsen to syncope, palpitations, and blue-purple ankle discoloration, and is accompanied by a marked decrease in systolic blood pressure, an increase in diastolic pressure, and tachycardia, all of which resolve when supine. We ascertained three families in which this disorder is inherited as an autosomal dominant trait with reduced penetrance. A genomewide scan was conducted in the two largest families, and three regions with multipoint LOD scores >1.5 were identified. Follow-up of these regions with additional markers in all three families yielded significant evidence of linkage at chromosome 18q. A maximum multipoint LOD score of 3.21 in the three families was observed at D18S1367, although the smallest family had negative LOD scores in the entire region. There was significant evidence of linkage in the presence of heterogeneity at 18q, with a maximum LOD score of 3.92 at D18S1367 in the two linked families. Identification of the gene responsible for orthostatic hypotensive disorder in these families may advance understanding of the general regulatory pathways involved in the continuum, from hypotension to hypertension, of blood pressure.

The role of delayed orthostatic hypotension in the pathogenesis of chronic fatigue.

Past studies have shown that severe fatigue was the presenting symptom in six of seven patients with delayed orthostatic hypotension and that tilt table-induced hypotension was found in 22 of 23 patients with the chronic fatigue syndrome. We have determined the prevalence of fatigue, volunteered in response to a nonspecific pre-examination questionnaire used in 431 patients, each subsequently diagnosed as having one of eight neurological or endocrine disorders. The results show that fatigue is a very common symptom in patients with delayed orthostatic hypotension (n = 21), as well as both primary (n = 30) and secondary (n = 106) hypocortisolism: 70-83% in all groups. In contrast, fatigue was an uncommon complaint in patients with multiple system atrophy (MSA) (n = 30), pituitary disorders without hypocortisolism (n = 106) or idiopathic hirsutism (n = 96): 7-33% in all groups, and was intermediate in prevalence in patients with acute hyperadrenergic orthostatic hypotension (n = 32): 41%. It is concluded that fatigue commonly results from delayed orthostatic hypotension and all forms of hypocortisolism but is less common in patients with acute orthostatic hypotension, both idiopathic and due to MSA, which more commonly present with lightheadedness or syncope.

Idiopathic intracranial hypertension and orthostatic edema may share a common pathogenesis.

Our aim was to determine the frequency of orthostatic edema (OE) in patients with idiopathic intracranial hypertension (IIH). We evaluated 30 women with IIH for evidence of OE by comparing sodium and water excretion in the recumbent and standing postures and morning and evening body weights. Data were compared with findings in 30 women with OE, 22 weight-matched obese normal subjects, and 20 lean normal subjects. The effect of treatment with diuretics or diuretics plus sympathomimetic agents was compared. Seventy-seven percent of IIH patients had evidence of peripheral edema and 80% had significant orthostatic retention of sodium or water. Excretion of a standard saline load and of a tap water load was significantly impaired in the upright posture in the IIH and OE patients compared with the lean and obese normal subjects. Diuretic therapy induced weight loss (up to 9 kg) and decreased mean weight gain from morning to evening in 5 of 12 patients treated. In seven patients also treated with diuretics plus sympathomimetic drugs, the diuretic-induced morning weight loss and morning to evening weight gain were both significantly improved with the addition of sympathomimetic agents. Therapy reduced the frequency or severity of headaches in seven patients and reduced papilledema in four patients who received no other concurrent treatment for IIH. The orthostatic retention of sodium and water and the consequent edema is very similar in IIH and OE patients, suggesting a common pathogenesis for both disorders. Diuretic therapy, dietary salt and water restriction, and planned periods of recumbency merit study as a treatment for these patients.

Suppressibility of plasma adrenocorticotropin by hydrocortisone: potential usefulness in the diagnosis of Cushing's disease.

Repeatedly normal cortisol suppressibility by dexamethasone in 2 patients with Cushing's disease led to the present study of the prevalence of this phenomenon in 58 patients with otherwise incontrovertible evidence of Cushing's disease. Because as many as 23% of these patients manifested this phenomenon, we investigated the suppressibility of plasma ACTH: 1) during i.v. infusion of hydrocortisone, after a priming dose (7 mg), at 3 mg/h in 8 patients and 8 normal controls; and 2) for 2 h, after oral hydrocortisone, 0.25 mg/kg, in 13 patients and 16 controls. The data showed invariable suppression of plasma ACTH to < or = 10 pg/mL (< or = 2.2 pmol/L) after 120 min of the infusion or at 90 min after oral hydrocortisone in 16 fasting normal subjects given oral hydrocortisone between 0800 and 0830 h. Plasma ACTH exceeded 10 pg/mL (2.2 pmol/L) at the same times in 14/14 patients with active Cushing's disease, including 3 patients whose cortisol suppressibility by dexamethasone had been misleadingly normal and in 4/7 patients with intermittent hypercortisolism. Occasional variations in plasma cortisol elevations after the oral dose require that plasma cortisol concentration be monitored at 60 min after the oral hydrocortisone dose, because the present evidence supports the validity of the conclusion that a plasma ACTH concentration below 10 pg/mL excludes Cushing's disease only when plasma cortisol concentration at 60 min lies between 16 and 38 microg/dL. Further evaluation of ACTH suppressibility by cortisol would be worthwhile, to confirm its potential value in facilitating positive diagnosis of Cushing's disease when dexamethasone suppressibility seems misleading.

A study of patients with Nelson's syndrome.

OBJECTIVE: The prevalence of Nelson's syndrome has varied greatly, at least in part because of the variability of the diagnostic criteria employed by different authors. We define Nelson's syndrome as the presence of an enlarging pituitary tumour associated with elevated fasting plasma ACTH levels and hyperpigmentation in patients with Cushing's disease after bilateral adrenalectomy. We have compared patients with Cushing's disease who developed Nelson's syndrome after bilateral adrenalectomy with those who did not. Our objective was to find differences between the two groups which might predict the development of Nelson's syndrome. PATIENTS AND METHODS: We have reviewed the records of 30 patients with Cushing's disease after adrenalectomy, and divided them into two groups; I: 14 who developed Nelson's syndrome and II, 16 who did not. The two groups of patients were compared in their clinical, laboratory and imaging data as well as in the therapeutic procedures that preceded the adrenalectomy. RESULTS: The comparison between the two groups of patients demonstrated a highly significant difference in relation to the development of cutaneous hyperpigmentation (100% in group I and 19% in group II) and neuro-ophthalmological symptoms (21% in group I and 0% in group II) after adrenalectomy. There were no significant differences in laboratory data before adrenalectomy. After adrenalectomy, plasma ACTH levels increased significantly in the patients of both groups, but to much higher levels in those who developed Nelson's syndrome. Plasma ACTH concentrations above 154 pmol/l occurred only in the subjects with Nelson's syndrome. Before adrenalectomy, a pituitary tumour was more frequent in the patients who developed Nelson's syndrome (55% vs. 33% at transsphenoidal pituitary exploration). Pituitary surgery and irradiation were undertaken before adrenalectomy in approximately equal numbers of patients in each group. DISCUSSION: The prevalence of Nelson's syndrome was 47% in our series of 30 patients with Cushing's disease after bilateral adrenalectomy. No clinical or laboratory data before adrenalectomy predicted the development of the syndrome. The value of prophylactic pituitary irradiation could not be evaluated from our clinical material. However, after adrenalectomy, the presence of hyperpigmentation and ACTH levels above 154 pmol/l had positive predictive value for the development of Nelson's syndrome. In this situation magnetic resonance imaging (MRI) of the pituitary is mandatory and, if no tumour is detected, MRI should be repeated at intervals.

Intermittent hypercortisolism: a disorder strikingly prevalent after hypophysial surgical procedures.

OBJECTIVE: To determine the frequency of intermittent hypercortisolism in a consecutive series of patients with Cushing's disease who underwent hypophysial surgical treatment. METHODS: Thirty-three patients with hypercortisolism of central origin underwent follow-up at approximately annual intervals for prolonged periods after a transsphenoidal pituitary surgical procedure. Clinical evaluation was done, and urinary steroid measurements, as well as dexamethasone suppression tests in some patients, were performed. RESULTS: Frequently normal but intermittently increased urinary 17-hydroxycorticosteroid or cortisol excretion (or both) was found in six patients postoperatively, associated with intermittently severe hypertension, headaches, and weakness in only one patient. In a seventh patient, intermittently excessive cortisol excretion was clearly evident preoperatively. CONCLUSION: Because corticoid excretion was variable preoperatively in three of the seven study patients, we conclude that intermittent hypercortisolism is commoner than previous evidence has shown, constitutes an extremely difficult diagnostic problem, and did not result from but failed to be cured by pituitary surgical treatment in 6 of 33 patients (18%). The findings emphasize the need for regular follow-up for several years in all patients with Cushing's syndrome who have undergone a hypophysial surgical procedure. Variable consistency of follow-up might partly explain the wide discrepancies between reports of 80 to 90% and 40 to 60% cure rates after a single hypophysial adenomectomy.

Hypokalemia in a patient with pheochromocytoma.

OBJECTIVE: To report the occurrence of hypokalemia in a patient with pheochromocytoma. METHODS: We present a case report and discuss the possible role of hyperepinephrinemia as a cause of hypokalemia. RESULTS: A patient with pheochromocytoma had hypokalemia associated with vomiting, but hypokalemia recurred after repletion of potassium and cessation of vomiting. She had substantially increased epinephrine concentrations in the plasma and in the subsequently excised pheochromocytoma. Because evidence has shown that infusions of epinephrine induce hypokalemia in normal human subjects, the relationship between serum potassium and plasma epinephrine concentrations in 16 previous patients with pheochromocytoma and 4 patients with primary hyperepinephrinemia was studied. A significant negative correlation was noted. CONCLUSION: The presence of hypokalemia and its potential role in predisposing to arrhythmias in patients with pheochromocytoma merit further study.

Mechanisms of orthostatic hypotension and tachycardia in patients with pheochromocytoma.

We have explored the pathophysiological mechanisms of orthostatic hypotension and orthostatic tachycardia, found to be present in 83% and 61% respectively of 18 patients with subsequently proven pheochromocytoma. Orthostatic increases in plasma norepinephrine (NE) concentrations were significantly greater in the patients than in normal control subjects. Intravenous infusions of NE at 1, 2, 4, 8, and 16 micrograms/min induced similar increases in plasma NE levels but smaller increments in systolic and diastolic BP in the pheochromocytoma patients than in normal control subjects. This was reflected by a significantly greater increment in plasma NE concentration required to raise systolic BP by 15 mm Hg and diastolic BP by 7 mm Hg in the pheochromocytoma patients than in the normal subjects (P < .05 and P < .01, respectively). Measurements of venous contractile responses to locally infused NE by the dorsal hand vein (LVDT) technique revealed significantly reduced slopes of the regressions of log NE infusion rate on change in venous diameter in the pheochromocytoma patients compared with normal subjects. The results indicate reduced responsiveness of the vasculature to NE in patients with pheochromocytoma, probably due to down-regulation of alpha-adrenergic receptors resulting from persistent elevation of the physiological agonist NE. This was shown by other authors to be present in circulating platelets. The pathophysiological importance of the subnormal venous responses to the orthostatic hypotension and tachycardia in the patients were supported by the finding that the orthostatic changes were corrected by lower body compression to 45 mm Hg with a MAST pressure suit.

Excessive gravitational blood pooling caused by impaired venous tone is the predominant non-cardiac mechanism of orthostatic intolerance.

1. In a group of 40 patients with orthostatic intolerance due to hypotension and/or tachycardia, we have compared the pathogenetic roles of impaired contractility of the arterioles and the veins by measuring contractile responsiveness of the arterioles, reflected by increases in diastolic blood pressure and of the veins reflected by measurements of reduction in venous diameter during intravenous noradrenaline infusions. 2. Compared with 27 healthy subjects, patients with diffuse autonomic insufficiency showed striking supersensitivity in diastolic blood pressure (six out of eight) and venous constrictive responses (seven out of eight patients) to noradrenaline, consistent with impaired arteriolar and venous innervation. 3. In contrast, the patients with hyperadrenergic orthostatic hypotension (n = 16) and orthostatic tachycardia (n = 16) showed diastolic blood pressure responses to noradrenaline that were almost invariably within the 95% confidence limits of the changes in normal subjects but supersensitive constrictive responses of foot veins in 22 of 32 subjects and subnormal venous responses in two individuals. The rate of noradrenaline infusion calculated to cause 50% of maximal venous constriction (the ED50) was significantly lower in the patients [mean (SEM) 6.8 (1.9) ng/min] than in the normal subjects [mean (SEM) 23.2 (3.0) ng/min, P < 0.025]. 4. The finding of significantly supersensitive foot vein constrictive responses to noradrenaline infusion in the patients of all three groups and supersensitive blood pressure responses exclusively in the patients with diffuse autonomic insufficiency indicates that venous pooling in the legs was the predominant pathogenetic mechanism of orthostatic intolerance in all three types of patients studied. 5. Correction of the orthostatic hypotension and/or tachycardia by external compression in virtually all patients confirmed this conclusion.

The potential for serious consequences from misinterpreting normal responses to the rapid adrenocorticotropin test.

Despite unequivocal published evidence that patients with subnormal hypothalamic-pituitary-adrenal (HPA) function may respond normally to ACTH, such normal results are still considered reliable indications of unimpaired HPA function. This view was tested in four patients with clinical features suggesting corticotropin deficiency, in whom cosyntropin (0.25 mg, i.v.) raised serum cortisol above 560 nmol/L (20 micrograms/dL) at 1 h. All four patients had subnormal responses to metyrapone and excellent persistent improvement during subsequent glucocorticoid therapy. Serum cortisol concentrations 1 h after cosyntropin treatment in these patients closely resembled cortisol concentrations 1 h after uncomplicated cholecystectomy in six other patients. However, the rapid ACTH test in the patients with hypopituitarism failed to indicate whether more prolonged stimulation by ACTH or their endogenous stress would stimulate the normal continuing rise in serum cortisol, which reached 1358 +/- 170 nmol/L (+/- SE) 5 h after the incision in the cholecystectomized patients. As the three hypocorticotropic patients who were recognizably stressed had unstressed serum cortisol levels despite persistent adrenocortical reserve (shown by their ACTH responses) and recovered during glucocorticoid therapy, the ACTH test, if interpreted to indicate normal HPA function, would probably have had disastrous consequences. We conclude that a normal response to the rapid ACTH test can be dangerously misleading, particularly in incomplete ACTH deficiency states.

Idiopathic edema. Pathogenesis, clinical features, and treatment.

Idiopathic edema is usually orthostatic. It is most evident in the feet or abdomen after prolonged standing or sitting and in the fingers and eyelids after recumbency overnight. It occurs almost exclusively in post-pubertal women and is associated with discomfort in the areas of fluid accumulation (including symptoms of the carpal tunnel syndrome, nonarticular rheumatism, and headaches, sometimes with pseudotumor cerebri), and weight gain with excessive increments from morning to evening. The pathogenesis, diagnosis, and treatment of idiopathic edema are discussed.