Anyway, I think that the clinical case is poorly stated, since before doing the CT scan, ACTH should be measured and, once ACTH is suppressed, the CT scan should be done. But since the question is "what would you do to confirm the diagnosis of suspected ACTH independent Cushing's syndrome", the answer is CT.

Anyway, I think that the clinical case is poorly stated, since before doing the CT scan, ACTH should be measured and, once ACTH is suppressed, the CT scan should be done. But since the question is "what would you do to confirm the diagnosis of suspected ACTH independent Cushing's syndrome", [HIDDEN].

In a 42-year-old obese woman, cortisol levels in blood, urine and saliva are determined and in all the determinations they are elevated. After performing the nocturnal suppression test with dexamethasone, cortisol levels in blood remain elevated, so ACTH independent Cushing's syndrome is suspected, what additional test would you request to confirm the diagnosis at this time?

A gammagraphy with labeled somatostatin (Octreoscan).

[Cushing's syndrome: diagnostic exploration].

The diagnosis of Cushing's syndrome is one of the most perplexing and controversial problems in endocrinology. However, significant advances in the diagnosis procedures have been made in the past decade. The diagnostic studies involved in the evaluation of patients with suspected Cushing's syndrome fall into two categories: confirming the presence of true hypercortisolism and establishing the precise aetiology. Diagnosis of Cushing's syndrome: ambulatory screening relies on the overnight 1 mg dexamethasone test. Negative tests are confirmed by measuring cortisol in two 24-hour urine samples. If cortisol excretion is slightly above normal, a 48-hour low-dose dexamethasone suppression test or an intravenous infusion dexamethasone suppression test are required. Diagnosis of the aetiology of Cushing's syndrome: the first step is to establish if the hypercortisolism is ACTH-dependent or not. This step is solved by measuring plasma ACTH and cortisol in the late afternoon. Computed tomography scanning of the adrenal glands is required in ACTH-independent Cushing's syndrome. A unilateral tumour will be demonstrated in most of cases. If bilateral lesions are found, dynamic testing using cortisol releasing factor and/or metyrapone must be performed to confirm the ACTH-independency of the syndrome. In ACTH-dependent Cushing's syndrome, the major difficulty is to distinguish between a pituitary source and an ectopic source of ACTH secretion. Magnetic resonance imaging of the pituitary with gadolinium enhancement must be preferred to computed tomography scanning but its sensitivity is not better than 70-80% and false positives can occur. When no macroscopic pituitary lesion can be detected, bilateral inferior petrosal sinus sampling coupled to CRH injection for ACTH measurement will indicate the source of ACTH secretion. If this test indicates the patient has Cushing's disease, pituitary trans-sphenoidal surgery can be performed. If the test indicates the patient has ectopic ACTH-secretion, a cervico-thoraco-abdominal scanning is necessary to identify the tumour. In the case of occult tumour the hypercortisolism must be controlled by pharmacological agents and the imaging investigations must be repeated at appropriate intervals.

Limitations of nocturnal salivary cortisol and urine free cortisol in the diagnosis of mild Cushing's syndrome.

Cushing's syndrome (CS) is difficult to diagnose due to its nonspecific presentation. Diagnostic tests like 24-h urine free cortisol (UFC) and the overnight 1 mg dexamethasone suppression test (DST) lack sufficient sensitivity and specificity. Measurement of nocturnal salivary cortisol (NSC) is an accurate and reproducible test with a high sensitivity for CS. However, its performance in mild CS has not been reported. We present 11 cases of CS with normal or mildly elevated UFC in whom NSC was helpful in making a diagnosis. All patients had at least one collection of 24-h UFC and NSC and eight had an overnight 1 mg DST. The number of NSC measurements per patient was determined by the clinical index of suspicion and the results of initial testing. Imaging studies included magnetic resonance imaging (MRI) of pituitary or computer tomography scan of abdomen. Only four out of eleven patients had elevations in UFC and none were >2 times the upper limit of normal. Seven out of eight had an abnormal DST. All patients had some elevated NSCs (14-100%). Out of eleven patients, six had an abnormality in the pituitary gland found by MRI and two out of eleven had adrenal masses. The remaining three had normal pituitary MRI but had inferior petrosal sinus (IPS) sampling indicating Cushing's disease. All patients had appropriate surgery, and histopathology of all except one was suggestive of either a cortisol-producing adrenal adenoma or an ACTH-secreting pituitary adenoma. Neither a normal UFC nor a normal NSC excludes mild CS. Multiple samples (urine/saliva) and DST are needed to make the diagnosis of mild CS.

[Rational diagnosis of endocrine forms of hypertension].

Primary aldosteronism, Cushing's syndrome and pheochromocytoma are the most frequent endocrine hypertensive disorders. Following biochemical confirmation of the clinical diagnosis, mainly non-invasive imaging techniques are necessary to determine the cause of the hormone excess. Diagnosis of primary aldosteronism is confirmed by analysis of aldosterone and renin in peripheral venous blood. Differentiation between adenoma and idiopathic adrenal hyperplasia usually is achieved by computed tomography and isotope scan. A reliable test for the biochemical confirmation of Cushing's syndrome is the determination of urine-free cortisol. In patients with equivocal results the dexamethasone suppression test is performed. Differential diagnosis between ACTH-dependent Cushing's syndrome (pituitary or ectopic) and primary adrenal disorders can be made by determination of plasma-ACTH and -cortisol. Non-invasive localization procedures include computed tomography of the abdomen, computed tomography or magnetic resonance imaging of the pituitary gland, sonography and isotope scan. Diagnosis of pheochromocytoma is based on elevated catecholamine levels in urine or plasma. The tumor is localized by ultrasound, computed tomography or isotope scan.

Subclinical Cushing's syndrome.

Classic Cushing's syndrome is a rare disease with an estimated incidence of 1 case per 100,000 persons. With routine use of imaging techniques such as ultrasound and CT, adrenal masses are being detected with increased frequency. A substantial percentage of these incidentalomas are hormonally active, with 5% to 20% of the tumors producing glucocorticoids. Autonomous glucocorticoid production without specific signs and symptoms of Cushing's syndrome is termed subclinical Cushing's syndrome. With an estimated prevalence of 79 cases per 100,000 persons, subclinical Cushing's syndrome is much more common than classic Cushing's syndrome. Depending on the amounts of glucocorticoids secreted by the tumor, the clinical spectrum ranges from slightly attenuated diurnal cortisol rhythm to complete atrophy of the contralateral adrenal gland with lasting adrenal insufficiency after unilateral adrenalectomy. Patients with subclinical Cushing's syndrome lack the classical stigmata of hypercortisolism but have a high prevalence of obesity, hypertension, and type 2 diabetes. All patients with incidentally detected adrenal masses scheduled for surgery must undergo testing for subclinical Cushing's syndrome to avoid postoperative adrenal crisis. The best screening test to uncover autonomous cortisol secretion is the short dexamethasone suppression test. Because the adrenal origin of a pathologic cortisol secretion is anticipated, the author prefers a higher dexamethasone dose (3 mg instead of 1 mg) to reduce false-positive results. A suppressed serum cortisol level of less than 3 micrograms/dL (80 nmol/L) after dexamethasone excludes significant cortisol secretion by the tumor. A serum cortisol level greater than 3 micrograms/dL requires further investigation, including confirmation by high-dose dexamethasone (8 mg) suppression testing, a CRH test, and analysis of diurnal rhythm. Determination of urinary free cortisol is less useful because increased values are a late finding usually associated with emerging clinical signs of Cushing's syndrome. Patients with suppressed plasma ACTH in response to CRH generally have adrenal insufficiency after surgery and require adequate perioperative and postoperative substitution therapy. Whether patients with subclinical Cushing's syndrome should undergo adrenalectomy is a matter of debate. The author performs surgery in young patients (< 50 years), in patients with suppressed plasma ACTH, and in patients with a recent history of weight gain, substantial obesity, arterial hypertension, diabetes mellitus, and osteopenia. In completely asymptomatic patients with normal plasma ACTH concentrations and in patients older than 75 years, the author recommends a nonsurgical approach. A large prospective randomized study is necessary to evaluate the benefits of surgery versus conservative treatment in patients with subclinical Cushing's syndrome.

Coexistence of Cushing Disease With a Solitary Adrenocorticotrophic Hormone-Dependent Adrenal Adenoma.

We report a 49-year-old woman who had minimal features of Cushing syndrome and an incidentally discovered adrenal adenoma. She was subsequently diagnosed with pituitary-dependent Cushing syndrome. Laboratory and imaging studies including serum cortisol, plasma adrenocorticotrophic hormone (ACTH), high dose dexamethasone test, corticotropin-releasing hormone test, computed tomography (CT) scan, and magnetic resonance imaging were performed. A 49-year-old woman was admitted for urosepsis. An abdominal CT scan performed during the urosepsis workup showed a 2.7-cm right adrenal adenoma. She denied any abdominal striae or other symptoms. Physical examination showed normal vital signs, minimal facial fullness without central obesity, and striae. Laboratory results were as follows: 24-hour-urine cortisol 294 μg (reference 4.0-50.0), midnight serum cortisol 23.0 μg/dL (reference < 7.5), and plasma ACTH level 39 pg/mL (reference 5-27). A corticotropin-releasing hormone stimulation test showed >20% rise in serum cortisol and >35% rise in ACTH levels. A pituitary magnetic resonance image showed a 5 mm pituitary lesion. The patient underwent transsphenoidal pituitary surgery, which confirmed an ACTH-secreting lesion. Postoperatively, she required hydrocortisone replacement for the next 10 months. A follow-up adrenal CT performed 6 months later showed a decrease in the size of the adrenal adenoma (1.8 cm). This case highlights the importance of recognizing the coexistence of ACTH-dependent Cushing disease with an adrenal adenoma and partial ACTH dependency of the adrenal adenoma.

Cushing's syndrome

When any of these tests is positive, CT scanning of the adrenal gland and MRI of the pituitary gland are performed to detect the presence of any adrenal or pituitary adenomas or incidentalomas (the incidental discovery of harmless lesions). Scintigraphy of the adrenal gland with iodocholesterol scan is occasionally necessary. Occasionally, determining the ACTH levels in various veins in the body by venous catheterization, working towards the pituitary (petrosal sinus sampling) is necessary. In many cases, the tumors causing Cushing's disease are less than 2 mm in size and difficult to detect using MRI or CT imaging. In one study of 261 patients with confirmed pituitary Cushing's disease, only 48% of pituitary lesions were identified using MRI prior to surgery. Plasma CRH levels are inadequate at diagnosis (with the possible exception of tumors secreting CRH) because of peripheral dilution and binding to CRHBP.

The differential diagnosis of Cushing's syndrome.

The diagnosis of Cushing's syndrome remains one of the most challenging tasks in clinical neuroendocrinology. The diagnostic procedure can be divided into two distinct steps: diagnosis of the neuroendocrine disorder and differential diagnosis of the precise aetiology. The goal of the first laboratory tests is to obtain biochemical proof of Cushing's syndrome. Patients with Cushing's syndrome are relatively insensitive to glucocorticoid feedback and exhibit an oversecretion of cortisol devoid of a circadian cycle. In our experience, a low-dose dexamethasone suppression test provides the most reliable confirmation of steroid resistance, a cortisol level of<50 nmol/l at 9 a.m. having 98% sensitivity. A cortisol level below 50 nmol/l at midnight rules out active Cushing's syndrome with, in our experience, 100% sensitivity and a specificity depending on numerous other variables. A very high level of free urinary corticol can be a useful sign. After having established the diagnosis of Cushing's syndrome, a persistently low level of ACTH (<10 pg/ml), or preferentially an undetectable level unresponsive to CRH (100 microgram iv), is suggestive of an ACTH-independent disorder, and consequently of primary adrenal disease. The precise location of the lesion can identified with CT or MRI imaging, generally prior to surgical cure. If the ACTH level is detectable, patients with pituitary Cushing's syndrome, or Cushing's disease, should be differentiated from those with ectopic ACTH secretion. The secreting tumour may be difficult to localise and diagnosis is never 100% sure with dynamic tests. Catheterisation of the petrosal sinus with CRH stimulation provides the best sensitivity for differentiating the two aetiologies. We consider a central to peripheral gradient of>3 to confirm the pituitary origin of the disorder with a 98% sensitivity. Chest or abdominal CT can be helpful to identify an ectopic tumour but very small tumours may go undetected. MRI can detect 60 or 70% of all pituitary adenomas but is virtually non-contributive to the diagnosis of Cushing's disease in children.

Cushing's syndrome

When Cushing's syndrome is suspected, either a dexamethasone suppression test (administration of dexamethasone and frequent determination of cortisol and ACTH level), or a 24-hour urinary measurement for cortisol offers equal detection rates. Dexamethasone is a glucocorticoid and simulates the effects of cortisol, including negative feedback on the pituitary gland. When dexamethasone is administered and a blood sample is tested, cortisol levels >50 nmol/l (1.81 μg/dl) would be indicative of Cushing's syndrome because an ectopic source of cortisol or ACTH (such as adrenal adenoma) exists which is not inhibited by the dexamethasone. A novel approach, recently cleared by the US FDA, is sampling cortisol in saliva over 24 hours, which may be equally sensitive, as late-night levels of salivary cortisol are high in cushingoid patients. Other pituitary hormone levels may need to be ascertained. Performing a physical examination to determine any visual field defect may be necessary if a

Preclinical Cushing's syndrome in adrenal "incidentalomas": comparison with adrenal Cushing's syndrome.

Adrenal tumors are usually diagnosed by clinical symptoms of hormone excess. The increasing use of ultrasound and computed tomography results in the detection of a substantial number of incidentally discovered adrenal tumors. Most of these tumors are nonfunctional adrenocortical adenomas, but a few cases of subclinical cortisol production in "incidentalomas" have been reported. We investigated prospectively the prevalence of autonomous cortisol production in 68 patients (44 females and 24 males, aged 25-90 yr) with adrenal incidentalomas at our institution. As a screening procedure all patients with incidentalomas underwent an overnight dexamethasone suppression test (1 mg). Patients who failed to suppress serum cortisol below 140 nmol/L (5 micrograms/dL) underwent more comprehensive studies (prolonged dexamethasone suppression test, determination of the diurnal rhythm of cortisol secretion in saliva, and CRH stimulation test). Eight patients (12% of all patients with incidentalomas; 5 females and 3 males, aged 25-71 yr) were finally identified as having cortisol-producing tumors, and the findings in these patients were compared with those of overt Cushing's syndrome in 8 patients (8 females, aged 26-50 yr) suffering from cortisol-producing adrenal adenomas. The tumor size of patients with cortisol-producing incidentalomas ranged from 2-5 cm. No specific signs and symptoms of hypercortisolism were present, but arterial hypertension (seven of eight subjects), diffuse obesity (four of eight subjects), and noninsulin-dependent diabetes mellitus (NIDDM; two of eight subjects) were frequently observed. Baseline cortisol levels were in the normal to upper normal range, whereas baseline ACTH levels were suppressed in five of the eight patients. In none of the patients was serum cortisol suppressible by low dose or high dose dexamethasone. The ACTH and cortisol responses to CRH were normal in two, blunted in one, and suppressed in four patients. Unilateral adrenalectomy was performed in seven patients and resulted in temporary adrenal insufficiency in four of them. After surgery, improvement of arterial hypertension, a permanent weight loss in obese subjects, and a better metabolic control of NIDDM were noted in the majority of patients. The following conclusions were reached. Incidentally diagnosed adrenal tumors with pathological cortisol secretion in otherwise clinically asymptomatic patients are more frequently observed than previously assumed. Adrenocortical insufficiency is a major risk in these patients after adrenalectomy. After surgery, hypertension, obesity, and NIDDM may improve. Patients with asymptomatic adrenal incidentalomas, therefore, should be screened for cortisol production by means of an overnight dexamethasone suppression test.

Primary pigmented nodular adrenocortical disease

Diagnosis Diagnosis usually occurs upon investigation of a cause for already suspected Cushing's syndrome. High levels of cortisol observed in patients with PPNAD are not suppressed upon administration of dexamethasone (dexamethasone suppression test), and upon MRI or CT imaging, the pituitary will show no abnormalities. Measuring ACTH will confirm that the cause of the patients Cushing's syndrome is ACTH independent. The nature of Cushing's syndrome itself is periodic, which can make diagnosing PPNAD increasingly difficult. Diagnosis of PPNAD can be difficult to determine preoperatively as CT scan findings can be variable i.e. appear normal or suggest unilateral adrenal lesions therefore impeding the correct diagnosis. NP-59 scintigraphy may be particularly useful in identifying the bilateral nature of the disease.

Assessment of cortisol and ACTH responses to the desmopressin test in patients with Cushing's syndrome and simple obesity.

The desmopressin test has recently been introduced in clinical practice as an adjunctive tool in the differential diagnosis of ACTH-dependent Cushing's syndrome (CS). It has been reported that the majority of patients with pituitary-dependent CS (Cushing's disease, CD) respond to desmopressin, while no such response is usually observed in other forms of this syndrome. In the present study, the responsiveness of the HPA axis to desmopressin was studied in a group of obese subjects. In addition, the ability of desmopressin administration to differentiate between patients with obesity and the various forms of Cushing's syndrome was investigated. Cortisol and ACTH responses to the administration of desmopressin (10 microg bolus i.v.) were examined in 20 consecutive patients with obesity (14 women and six men; BMI range: 34.5-66.7 kg/m2). Obese subjects had no clinical stigmata of CS. In all obese patients, either an overnight (dex 1 mg at 2300 h) (n = 8) or a formal low-dose (dex 0.5 mg 6-hourly for 2 days) (n = 12) dexamethasone suppression test was performed for the exclusion of Cushing's syndrome. Three of eight subjects showed failure of cortisol suppression (i.e. F > 28 nmol/l) to the overnight dexamethasone suppression test, but they had undetectable cortisol levels (< 28 nmol/l) on further testing with the formal 2-day test. All but two of the remaining subjects had undetectable cortisol levels (< 28 nmol/l) following the formal 2-day, low-dose, dexamethasone suppression test. For comparison, desmopressin responses were also tested in 33 patients with CS of varied aetiologies (25 patients with pituitary-dependent CS, three patients with occult ectopic ACTH secretion and five patients with primary adrenal CS). A positive response was considered to be an increment greater than 20% and 50% from baseline levels of cortisol and ACTH, respectively. Mean cortisol (F) and ACTH levels did not differ from the baseline at any time point following desmopressin administration in the obese group (basal F: 417 +/- 41, peak F: 389 +/- 32 nmol/l, P > 0.05; basal ACTH: 33.5 +/- 4.3, peak ACTH: 50.6 +/- 16.6 ng/l, P > 0.05), or in patients with occult ectopic or primary adrenal CS. In contrast, in the group of patients with CD, there was a significant rise in the mean ACTH and F levels from baseline (basal F: 725 +/- 50, peak F: 1010 +/- 64 nmol/l, P < 0.01; basal ACTH: 88.6 +/- 11.8, peak ACTH: 351 +/- 64 ng/l, P < 0.01). Cortisol responses greater than 20% from baseline were observed in 21/25 (84%) patients with CD, but in only 3/20 (15%) of the obese patients. With regard to ACTH, increments greater than 50% over baseline were observed in 23/25 (92%) of patients with CD, and in only 3/20 (15%) of the obese patients. As previously reported, none of the patients with occult ectopic ACTH secretion or primary adrenal CS had a positive response. The prevalence of subjects who met the criteria adopted to define positive cortisol and ACTH responses to the desmopressin test was significantly higher in the group of patients with Cushing's disease than in the group of patients with obesity. It is therefore suggested that this test may be occasionally useful in the differentiation between simple obesity and the pituitary-dependent form (but not other forms) of Cushing's syndrome.

Cushing's disease

Diagnosis Diagnosis is made first by diagnosing Cushing's syndrome, which can be difficult to do clinically since the most characteristic symptoms only occur in a minority of patients. Some of the biochemical diagnostic tests used include salivary and blood serum cortisol testing, 24-hour urinary free cortisol (UFC) testing, the dexamethasone suppression test (DST), and bilateral inferior petrosal sinus sampling (IPSS or BIPSS for bilateral IPSS). No single test is perfect and multiple tests should always be used to achieve a proper diagnosis. Diagnosing Cushing's disease is a multidisciplinary process involving doctors, endocrinologists, radiologists, surgeons, and chemical pathologists.

Dexamethasone suppression test

Test Procedures There are several types of DST procedures: Overnight DST - An oral dose of dexamethasone is given between 11pm and midnight, and the cortisol level is measured at 8 - 9am the next morning Two-day DST - This involves giving an oral dose of dexamethasone at six-hourly intervals for 2 days, with the cortisol level measured 6 hours after the final dose was given Intravenous DST Dexamethasone-CRT test Interpretation Low-dose and high-dose variations of the test exist. The test is given at low (usually 1–2 mg) and high (8 mg) doses of dexamethasone, and the levels of cortisol are measured to obtain the results. A low dose of dexamethasone suppresses cortisol in individuals with no pathology in endogenous cortisol production. A high dose of dexamethasone exerts negative feedback on pituitary neoplastic ACTH-producing cells (Cushing's disease), but not on ectopic ACTH-producing cells or adrenal adenoma (Cushing's syndrome).

Dexamethasone suppression test

Dose A normal result is a decrease in cortisol levels upon administration of low-dose dexamethasone. Results indicative of Cushing's disease involve no change in cortisol on low-dose dexamethasone, but inhibition of cortisol on high-dose dexamethasone. If the cortisol levels are unchanged by low- and high-dose dexamethasone, then other causes of Cushing's syndrome must be considered with further work-up necessary. After the high-dose dexamethasone, it may be possible to make further interpretations. †ACTH as measured prior to dosing of dexamethasone Equivocal results should be followed by a corticotropin-releasing hormone stimulation test, with inferior petrosal sinus sampling. References Theodore C. Friedman, M.D., Ph.D. Professor of Medicine-UCLA Chairman, Department of Internal Medicine Charles R. Drew University (2013). http://www.goodhormonehealth.com/talks/cushings-MAGIC-13.ppt Endocrine procedures Dynamic endocrine function tests

Cushing's syndrome

Cushing's syndrome is caused by either excessive cortisol-like medication, such as prednisone, or a tumor that either produces or results in the production of excessive cortisol by the adrenal glands. Cases due to a pituitary adenoma are known as Cushing's disease, which is the second most common cause of Cushing's syndrome after medication. A number of other tumors, often referred to as ectopic due to their placement outside the pituitary, may also cause Cushing's. Some of these are associated with inherited disorders such as multiple endocrine neoplasia type 1 and Carney complex. Diagnosis requires a number of steps. The first step is to check the medications a person takes. The second step is to measure levels of cortisol in the urine, saliva or in the blood after taking dexamethasone. If this test is abnormal, the cortisol may be measured late at night. If the cortisol remains high, a blood test for ACTH may be done.

Surgery_Schwartz

is diagnostic 1) Overnight DST2) 24-hour urinary free cortisol3) 11:00 pm salivary cortisol1) Plasma ACTH2) High-dose DST and urinary cortisolConfirm the diagnosisACTH gradient?Determine source of hypercortisolismDecreased ACTHLack of suppressionCT scan adrenalsIncreased ACTHPositive Increased ACTHLack of suppressionEquivocalresultsFurther testingBilateral petrosalvein samplingAdrenalsourcePituitarysourceEctopic ACTHsourceSTEPS IN DIAGNOSISDIAGNOSTIC STUDIESYesNoFigure 38-44. Diagnosis of Cushing’s syndrome. ACTH = adrenocorticotropic hormone; CT = computed tomography; DST = dexamethasone suppression test.Brunicardi_Ch38_p1625-p1704.indd 169001/03/19 11:22 AM 1691THYROID, PARATHYROID, AND ADRENALCHAPTER 38of a pituitary tumor. In patients suspected of having ectopic ACTH production, CT or MRI scans of the chest and anterior mediastinum are performed first, followed by imaging of the neck, abdomen, and pelvis if the initial studies are negative.Treatment Laparoscopic

Pseudo-Cushing's syndrome

Diagnosis Levels of cortisol and ACTH both elevated 24-hour urinary cortisol levels elevated Dexamethasone suppression test Late night salivary cortisol (LNSC) Loss of diurnal variation in cortisol levels (seen only in true Cushing's Syndrome) High mean corpuscular volume and gamma-glutamyl transferase may be clues to alcoholism Polycystic Ovarian Syndrome should be ruled out; PCOS may have similar symptoms

Surgery_Schwartz

Measurement of elevated 24-hour urinary cortisol levels is a very sensitive (95–100%) and specific (98%) modality of diagnosing Cushing’s syndrome and is particularly useful for identifying patients with pseudo-Cushing’s syn-drome. A urinary cortisol-free excretion of less than 100 μg/dL (in most laboratories) rules out hypercortisolism. Recently, salivary cortisol measurements using commercially available kits also have demonstrated superior sensitivity in diagnosing Cushing’s syndrome and are being increasingly used. Overall, 24-hour urinary tests for free cortisol and the overnight dexa-methasone suppression test at the 5 μg/dL cutoff have the high-est specificity for the diagnosis of Cushing’s syndrome.103Once a diagnosis of hypercortisolism is established, further testing is aimed at determining whether it is ACTH-dependent or ACTH-independent Cushing’s syndrome. This is best accom-plished by measurement of plasma ACTH levels (normal 10–100 pg/mL). Elevated ACTH levels are found

Recent challenges in the diagnosis of Cushing's syndrome.

The diagnosis of Cushing's syndrome still represents a challenge for the endocrinologist. Correct implementation and interpretation of diagnostic procedures require expertise and a high degree of clinical knowledge. The diagnosis should be established based on results of two or more concordant first-line tests (e.g., urinary free cortisol, midnight serum cortisol and low-dose dexamethasone testing); otherwise, second-line tests such as the dexamethasone-suppressed corticotrophin-releasing hormone (CRH) test, desmopressin stimulation or later reevaluation can confirm/exclude the diagnosis. Aetiological diagnosis requires measurement of plasma corticotrophin (ACTH) to distinguish between ACTH-dependent (pituitary or extrapituitary ACTH-secreting tumors) and ACTH-independent Cushing's syndrome (adrenal cortisol-secreting lesions), and the possible detection of normal ACTH levels in patients with adrenal Cushing's syndrome must be kept in mind. Lastly, the differential diagnosis between pituitary and ectopic ACTH secretion can be performed using CRH testing, high-dose dexamethasone suppression and inferior petrosal sinus sampling. The different epidemiology of the two entities and the incomplete diagnostic accuracy of diagnostic procedures mandate careful evaluation of test results.

Diagnostic approach to Cushing disease.

In Cushing disease, a pituitary corticotroph neoplasm causes secondary adrenal hypercortisolism. This condition has known morbidity and mortality, underscoring the need for an efficient and accurate diagnostic approach. An 11 p.m. salivary cortisol level is a modern, simple initial screening tool for the diagnosis of Cushing syndrome. Confirmation with a 24-hour urinary free cortisol test and/or a low-dose dexamethasone suppression test may subsequently be performed. Patients with repeatedly equivocal results should be reevaluated after several months or undergo a corticotropin-releasing hormone (CRH) stimulation test following low-dose dexamethasone suppression to help rule out pseudo-Cushing states. The presence of low morning serum adrenocorticotropic hormone (ACTH) levels then distinguishes primary adrenal hypercortisolism from Cushing disease and the ectopic ACTH syndrome. Patients with moderate ACTH levels can undergo CRH stimulation testing to clarify the underlying disease because those with an ACTH-independent disorder have blunted subsequent ACTH levels. Once ACTH-dependent hypercortisolemia is detected, magnetic resonance (MR) imaging of the pituitary gland can be performed to detect a pituitary neoplasm. Normal or equivocal MR imaging results revealing small pituitary lesions should be followed up with inferior petrosal sinus sampling, a highly specific measure for the diagnosis of Cushing disease in experienced hands. If necessary, body imaging may be used in turn to detect sources of ectopic ACTH.

Addison's disease

Testing In suspected cases of Addison's disease, demonstration of low adrenal hormone levels even after appropriate stimulation (called the ACTH stimulation test or synacthen test) with synthetic pituitary ACTH hormone tetracosactide is needed for the diagnosis. Two tests are performed, the short and the long test. Dexamethasone does not cross-react with the assay and can be administered concomitantly during testing. The short test compares blood cortisol levels before and after 250 micrograms of tetracosactide (intramuscular or intravenous) is given. If one hour later, plasma cortisol exceeds 170 nmol/l and has risen by at least 330 nmol/l to at least 690 nmol/l, adrenal failure is excluded. If the short test is abnormal, the long test is used to differentiate between primary adrenal insufficiency and secondary adrenocortical insufficiency.

Ectopic ACTH-secreting syndrome: a single center experience report with a high prevalence of occult tumor.

Differentiation between the two forms of ACTH-dependent Cushing's syndrome is a challenging task. Although the majority of these cases will be diagnosed as Cushing's disease secondary to an ACTH-secreting pituitary adenoma, 10-15% result from the ectopic ACTH secretion syndrome (EAS), which is usually due to neuroendocrine tumors. In the present study we report our experience with EAS in eight patients evaluated and treated during the past 10 years. Our experience in the evaluation and management of EAS was retrospectively reviewed. The latter included a standard biochemical assessment (urinary free cortisol, low- and high-dose dexamethasone suppression tests), petrosal sinus sampling when indicated and imaging techniques such as pituitary MRI, total body CT and somatostatin receptor scintigraphy. The ectopic nature of the ACTH hypersecretion was confirmed with inferior petrosal sinus samplings in all cases. CT scanning localized a putative tumor in 6/8 patients, whereas octreotide scintigraphy was positive in only five. In all cases, the source was traced to the lungs. However, upon performing thoracotomy, a documented ACTH-secreting bronchial carcinoid tumor was found in only four patients. Thus, 4/8 patients with EAS remained "occult." All of these patients underwent adrenalectomy for hypercortisolism control. EAS is a rare cause of ACTH-dependent Cushing's syndrome. Truly "occult" tumors were frequent and these patients need to be under close surveillance for the detection of neuroendocrine tumors.

Adrenal tumor

In these cases, a dexamethasone suppression test is often used to detect cortisol excess, and metanephrines or catecholamines for excess of these hormones. Tumors under 3 cm are generally considered benign and are only treated if there are grounds for a diagnosis of Cushing's syndrome or pheochromocytoma. Radiodensity gives a clue in estimating malignancy risk, wherein a tumor with 10 Hounsfield units or less on an unenhanced CT is probably a lipid-rich adenoma. Hormonal evaluation includes: 1-mg overnight dexamethasone suppression test 24-hour urinary specimen for measurement of fractionated metanephrines and catecholamines Blood plasma aldosterone concentration and plasma renin activity, if hypertension is present

[The diagnosis of Cushing's syndrome. Results of diagnostic assessment of 20 patients with Cushing's syndrome of variable etiology (1979-1989)].

In the light of 20 cases of Cushing's syndrome the currently used diagnostic strategies are presented. For initial screening the classical dexamethasone suppression test using 1 mg dexamethasone p.o. and 24-hour urinary extraction of free cortisol were used, and diagnosis was confirmed using the 2 mg dexamethasone suppression test for two days. All three tests had a sensitivity of 100% in these 20 patients. Etiological evaluation was performed using basal ACTH plasma concentration measurement and the more recently available stimulation tests using corticotropin-releasing factor (CRF): in cases with suspected pituitary-hypothalamic etiology, selective catheterisation of the sinus petrous inferior with simultaneous blood sampling for measurement of plasma ACTH concentration was performed. Detailed etiological diagnosis is important in Cushing's syndrome since therapeutic measures differ widely: the etiologies in the 20 patients with Cushing's syndrome were: central Cushing's disease (microadenoma in 11, pituitary carcinoma in 1), adrenal carcinoma (3), adrenal adenoma (1), adrenal hyperplasia (1), ectopic ACTH production (2) and alcohol-induced Cushing's syndrome (1). The stepwise procedure in screening and diagnosis of the various etiologies of Cushing's syndrome are presented and the results of the 20 patients compared with the literature.

Surgery_Schwartz

determining whether it is ACTH-dependent or ACTH-independent Cushing’s syndrome. This is best accom-plished by measurement of plasma ACTH levels (normal 10–100 pg/mL). Elevated ACTH levels are found in patients with adrenal hyperplasia due to Cushing’s disease (15–500 pg/mL) and those with CRH-secreting tumors, but the highest levels are found in patients with ectopic sources of ACTH (>1000 pg/mL). In con-trast, ACTH levels are characteristically suppressed (<5 pg/mL) in patients with primary cortisol-secreting adrenal tumors. The high-dose dexamethasone suppression test is used to distinguish between the causes of ACTH-dependent Cushing’s syndrome (pituitary vs. ectopic). The standard test (2 mg dexamethasone every 6 hours for 2 days) or the overnight test (8 mg) may be used, with 24-hour urine collections for cortisol and 17-hydroxy steroids performed over the second day. Failure to suppress urinary cortisol by 50% confirms the diagnosis of an ectopic ACTH-producing tumor. Patients

[Cushing's syndrome. I. New diagnostic developments].

Over the past few years, new diagnostic tests for Cushing's syndrome have become available. Some of the other, older diagnostic tests have fallen into discredit as they could not distinguish conditions from one another sufficiently well. New biochemical tests include midnight salivary cortisol measurement and the combined dexamethasone-corticotropin releasing hormone (CRH) test. The high dose dexamethasone test and the CRH-stimulation test have been abandoned as they were unable to differentiate between hypophysial and ectopic secretion of adrenocorticotropic hormone (ACTH). For the detection of ectopic ACTH-secreting tumours new imaging techniques, such as somatostatin receptor scintigraphy and positron emission tomography with 5-hydroxytryptophan, have become available.

Low Diagnostic Utility of Overnight High-Dose Dexamethasone Suppression Test in ACTH-Dependent Cushing's Syndrome.

Overnight high-dose dexamethasone suppression test (ON-HDDST) is a simple test to localize the source of ACTH in patients with ACTH-dependent Cushing's syndrome (CS). However, previous studies have reported its varying accuracy. We studied the utility of ON-HDDST in diagnosing Cushing's disease (CD) in a series of patients with CD and ectopic ACTH syndrome (EAS). We conducted a retrospective study of 88 patients with ACTH-dependent CS (plasma ACTH > 20.0 pg/mL), who underwent an ON-HDDST. CD and EAS were diagnosed in 68 and 20 patients, respectively. Patients were investigated using MRI of the sellar region, CT of the thorax/abdomen, Gallium-68-DOTANOC PET scan, and bilateral inferior petrosal sinus sampling as required. Patients with EAS had a significantly higher serum cortisol after ON-HDDST than patients with CD (median [IQR], 19.9 [12.4-31.1] μg/dL vs 9.9 [5.1-25.0] μg/dL, P <.01). A suppressed ON-HDDST (≥50% fall from baseline) was noted in 44 (65%) patients with CD and 3 (15%) patients with EAS (P <.0001). Among patients with CD, cortisol suppression >50% was noted in 35 (76%) of patients with microadenoma and 7 (44%) with macroadenoma. Among patients with EAS, ON-HDDST was suppressed in 1 of 6 patients (17%) with an occult tumor and 2 of 14 patients (14%) with a localized tumor. The ROC curve plotted for the percentage suppression of cortisol had an area under the curve (AUC) of 0.72 (P =.01). The best test parameters, with 65% sensitivity, 85% specificity, 94% positive predictive value, 42% negative predictive value, and 69% accuracy, were at 50% cutoff level. The ON-HDDST had a poor diagnostic value in differentiating CD and EAS.

Diagnostic workup of Cushing's syndrome.

Cushing's syndrome (CS) is a rare but detrimental endocrine disorder. Early diagnosis and prompt treatment are essential since the duration of hypercortisolism has an adverse impact on the extent of comorbidities and overall survival. The diagnostic approach involves a stepwise process that includes (1) screening and confirming the diagnosis and (2) establishing the aetiology of CS. The tests currently used to confirm the diagnosis of CS include urinary free cortisol measurements, the dexamethasone suppression test and late- night salivary cortisol or midnight serum cortisol measurements. None of these tests are ideal; all have pitfalls and require careful interpretation. Following confirmation of CS, measurement of ACTH discriminates between ACTH-dependent and non-ACTH dependent causes of CS. Adrenal imaging provides clues for the aetiology of non-ACTH dependent forms. Differentiation between the ACTH-dependent forms that involve pituitary corticotroph adenomas and ectopic ACTH sources is more complex and include pituitary MRI imaging, the high dose dexamethasone suppression test, the CRH test, bilateral inferior petrosal sinus sampling and, when required imaging modalities to detect ectopic ACTH secreting lesions. This review, which is part of a special issue on "Update of Cushing's syndrome: 100 years after Minnie G" will provide an update on our current diagnostic workup for the confirmation and differential diagnosis of CS.

The Cushing syndrome: an update on diagnostic tests.

Review and evaluation of diagnostic tests for the Cushing syndrome based on reports published since 1978. Studies published in the English literature from 1978 through 1989 were identified using Index Medicus and cross searching of bibliographies. Studies of five or more patients for general analysis and smaller studies and case reports when pertinent. To develop criteria for the corticotropin-release hormone (CRH) stimulation test, only studies reporting individual patient data were analyzed. No new test is clearly better than existing tests in establishing a definitive diagnosis. Among tests to determine cause, the CRH stimulation test, by newly developed criteria, has a 91% sensitivity (95% CI, 85% to 95%) and a 95% specificity (CI, 82% to 99%), and the overnight high-dose dexamethasone suppression test has an 89% sensitivity (CI, 80% to 94%) and a 100% specificity (CI, 84% to 100%) for the pituitary Cushing syndrome. Magnetic resonance imaging has greater sensitivity for detecting adrenocorticotropin (ACTH)-producing pituitary adenomas than computed tomography. Inferior petrosal sinus sampling can correctly identify a pituitary cause in 88% (CI, 79% to 94%) of cases. Diagnosis is still best established by using 24-hour urine free cortisol measurements or low-dose dexamethasone suppression testing. The CRH stimulation test is an outpatient alternative to determine cause, and the over-night high-dose dexamethasone test may become the test of choice along with plasma ACTH measurements by radioimmunoassay in the initial evaluation of cause. Magnetic resonance imaging should be used to evaluate the pituitary Cushing syndrome, and inferior petrosal sinus sampling is most useful in problematic cases with uncertain cause.

Adrenocorticotrophin-dependent hypercortisolism: imaging versus laboratory diagnosis.

Cushing's syndrome results from inappropriate exposure to excessive glucocorticoids. Untreated, it has significant morbidity and mortality. A 38-year-old woman with a typical appearance of Cushing's syndrome was admitted for further evaluation of hypercortisolism. The serum cortisol level was elevated without diurnal rhythm, without adequate suppression of cortisol after 1 mg dexamethasone suppression test. 24-hour urinary-free cortisol level was elevated. Differential diagnostic testing indicated adrenocorticotrophin (ACTH)-dependent lesion of the pituitary origin. Pituitary abnormalities were not observed during repeated MRI scanning. Inferior petrosal sinus sampling (IPSS) was performed: 1) Baseline ratio ACTH inferior petrosal sinus/peripheral was <2; 2) Corticotropin-releasing hormone (CRH) stimulated ratio ACTH inferior petrosal sinus/peripheral was <3; 3) Baseline intersinus ratio of ACTH was <1.4; 4) Increase in inferior petrosal sinus and peripheral ACTH of more than 50 percent above basal level after CRH; 5) Baseline ratio ACTH vena jugularis interna/peripheral was >1.7. Transsphenoidal exploration and removal of the pituitary tumor was performed inducing iatrogenic hypopituitarism. Postoperative morning serum cortisol level was less than 50 nmol/l on adequate replacement therapy with hydrocortisone, levothyroxine and estro-progestagen. No single test provides absolute distinction, but the combined results of several tests generally provide a correct diagnosis of Cushing's syndrome.

InternalMed_Harrison

Pos. Neg. Neg. Adrenal tumor workup Differential diagnosis 1: Plasma ACTH ACTH normal or high>15 pg/ml CRH test and highdose DEX positive ACTH suppressed to <5 pg/ml ACTH-dependent Cushing’s ACTH-independent Cushing’s Bilateral micronodular or macronodular adrenal hyperplasia Bilateral adrenal-ectomy Unilateral Unilateral adrenal mass CRH test and highEquivocal adrenal-ectomy Differential diagnosis 2 • MRI pituitary Unenhanced CT• CRH test (ACTH increase >40% at 15-30 min + cortisol increase >20%at 45-60 min after CRH 100 µg IV)• High dose DEX test (Cortisol suppression >50% after q6h 2 mg DEX for 2 days) Trans-Inferior petrosal sinus sampling Locate and sphenoidal(petrosal/peripheralremove surgery ACTH ratio >2 atbaseline, >3 at 2–5 minectopic after CRH 100 µg i.v.) source ACTH Ectopic ACTH production Cushing’s disease pituitary dose DEX negative results adrenals

[Image diagnosis of adrenal disorders--II. Cushing's syndrome].

Comparative study of image diagnosis of ultrasonography (US) by linear electronic scanner, computed tomography (CT), and adrenal scintigraphy was performed in 14 patients with Cushing's syndrome. Adrenal imaging by scintigraphy was performed at the 5th and 6th day or further 7th day following the injection of 1 mCi of Adosterol. Cushing's disease (11 cases) US failed to detect the adrenals in 4 cases examined. Measurement of the adrenals on CT film demonstrated the enlargement of adrenals (greater than mean + 2SD) in 6 of 7 cases (85.7%). Scintiscanning showed the increased uptake of bilateral adrenals in 4 of 10 cases (40%). Adrenal scintigraphy with dexamethasone pretreatment (DP) still demonstrated the isotope uptake of bilateral adrenals in all of those 4 cases tested, although the other 6 cases were not studied with DP. From these findings, it was suggested that the measurement of adrenal size by CT was useful for the additional image diagnosis of Cushing's disease, and the adrenal scintigraphy with DP was also available for complementary study of Cushing's disease. Cushing's syndrome due to adrenocortical adenoma (3 cases) In one case examined by US, which had the smallest adenoma (0.6 X 1.0 X 2.0 cm) in this syndrome, the adenoma was not detected. All of 3 adrenal adenomas (2.6 X 2.6 X 2.2 cm to 0.6 X 1.0 X 2.0 cm) were detected by CT. Adrenal scintigraphy demonstrated good uptake by adrenal adenoma but no visualization of the contralateral adrenal in every case.


Patient with suspected meningococcal sepsis. Stabilization with fluids (hypotension) according to ABCDE is essential. Blood culture can be obtained together with the initial blood test. Early initiation of antibiotic therapy (cefotaxime) is essential. However, in an unstable patient such as ours, a lumbar puncture is not indicated.

A 23-month-old boy presenting with fever, hypotension, repeated vomiting, meningeal signs, petechiae, and ecchymosis. The CBC shows 25,000 leukocytes (75% neutrophils, 10% white blood cells) and 12,000 platelets/microL, and the coagulation study shows a prothrombin activity of 35%. Which option is NOT appropriate for management?

[Meningococcemia: Different Serotypes in the Same Region].

Meningococcal infections are important health problems causing high morbidity and mortality. Neisseria meningitidis have 13 serogroups. A, B, C, Y and W135 are the most common causes of invasive disease among those serogroups. The distribution of the serogroups differs according to the geographical regions and the age groups. In this case report, two cases of meningococcemia infected with serogroup C and Y of N.meningitidis rarely seen in our country were presented. First case was a two and a half year-old female patient who has admitted to our pediatric emergency unit with fever and rash spreading from lower extremities to her body. The patient had diffuse purpuric rash with generalized weakness and tendency to sleep at admission. The patient has been suspected as meningococcemia because of the skin rash, tendency to sleep and hypotension. Antibiotics treatment was started immediately and lumber puncture was performed. In blood tests, leukocyte count: 3600/mm3 (61% neutrophils), hemoglobin: 11.1 g/ dl, platelet count: 127.000/mm3 , C-reactive protein: 10 mg/dl, erythrocyte sedimentation rate: 6 mm/ hour, prothrombin time: 28.8 seconds (normal value= 11-16), prothrombin activity: 36%, international normalized ratio (INR): 2.13 (normal value= 1-1.5), activated partial thromboplastin time: 57.7 seconds (normal value= 25-35 sec), fibrinogen: 246 mg/dl (normal value= 200-400 mg/dl) and in cerebrospinal fluid protein: 21 mg/dl and glucose: 62 mg/dl were found. There were eight cells in the microscopic examination. Skin rashes were increased and the patient became hypotensive. No microorganisms were isolated in blood and cerebrospinal cultures. N.meningitidis serogroup C was isolated from the cerebrospinal fluid of the patient using polymerase chain reaction (PCR). The patient suffered from immune-mediated arthritis in the sixth day of treatment and nonsteroidal anti-inflammatory drugs were given. The patient has recovered with antibiotics, fresh frozen plasma and inotropic treatment. Second case was a 13 year-old male patient who has admitted three days after the first case with a pre-diagnosis of malignancy because of pancytopenia and fever. The patient had generalized weakness and a few petechial purpuric rashes at the facial region at admission. After the admission general status of the patient has worsened rapidly and he has died as a result of cardiovascular arrest. Blood tests in admission showed leukocyte count: 6000/mm3 (79% neutrophils), hemoglobin: 17.3 mg/dl, platelet count: 16.000/mm3 , C-reactive protein: 8.63 mg/dl, prothrombin time: 92.6 seconds, prothrombin activity: 10%, INR: 6.78, activated partial thromboplastin time: 231.5 seconds. Cerebrospinal fluid obtained from postmortem lumbar puncture showed no growth (protein: 95 mg/dl, glucose: 35 mg/dl) and N.meningitidis serogroup Y was detected by PCR. Two meningococcemia cases caused by two different serogroups which are rarely seen in our region in recent years were presented at the same time period in the same hospital. This case report pointed out that surveillance has a great importance in such diseases.

A child with spider bite and glomerulonephritis: a diagnostic challenge.

A previously healthy 7-year-old white boy presented to St. Louis Children's Hospital with a 1-day history of headache, malaise, temperature of 38.7 degrees C, and a progressively erythematous, tender calf with central dusky purpura. On the morning of admission, his mother noticed a 2-mm crust on the patient's right calf with a 3-cm x 3-cm area of surrounding erythema. No history of recent trauma or bite was obtained. He had suffered two episodes of nonbloody, nonbilious emesis during the last day. In addition, over the previous 12 h, he presented brown urine without dysuria. His mother and brother had suffered from gastroenteritis over the previous week without bloody diarrhea. On initial physical examination, there was a 6-cm x 11-cm macular tender purpuric plaque with a central punctum on the right inner calf, which was warm and tender to the touch, with erythematous streaking towards the popliteal fossa (Fig. 1). The inguinal area was also erythematous with tender lymphadenopathy and induration, but without fluctuance. Laboratory studies included an elevated white blood cell count of 20, 800/microL with 6% bands, 86% segs, and 7% lymphocytes, hemoglobin of 12.5 g/dL, hematocrit of 35.1%, and platelets of 282,000/microL. The prothrombin time/activated partial tissue thromboplastin was 10. 4/28.0 s (normal PT, 9.3-12.3 s; normal PTT, 21.3-33.7 s) and fibrinogen was 558 mg/dL (normal, 192-379 mg/dL). Urinalysis showed 1+ protein, 8-10 white blood cells, too numerous to count red blood cells, and no hemoglobinuria. His electrolytes, blood urea nitrogen (BUN), and creatine were normal. The urine culture was negative. Blood culture after 24 h showed one out of two bottles of coagulase negative Staphylococcus epidermidis. The patient's physical examination was highly suggestive of a brown recluse spider bite with surrounding purpura. Over the next 2 days, the surrounding rim of erythema expanded. The skin within the plaque cleared and peeled at the periphery. The coagulase negative staphylococci in the blood culture were considered to be a contaminant. Cefotaxime and oxacillin were given intravenously. His leg was elevated and cooled with ice packs. The patient's fever resolved within 24 h. The lesion became less erythematous and nontender with decreased warmth and lymphadenopathy. The child was discharged on Duricef for 10 days. Because the patient experienced hematuria rather than hemoglobinuria, nephritis was suggested. In this case, poststreptococcal glomerulonephritis was the most likely cause. His anti-streptolysin-O titer was elevated at 400 U (normal, <200 U) and C3 was 21.4 mg/dL (normal, 83-177 mg/dL). His urine lightened to yellow-brown in color. His blood pressure was normal. Renal ultrasound showed severe left hydronephrosis with cortical atrophy, probably secondary to chronic/congenital ureteropelvic junction obstruction. His right kidney was normal.

[A report of two children with fever, headache, and purpura].

In this study, two school-aged children had an acute onset in spring and had the manifestations of fever, headache, vomiting, disturbance of consciousness, purpura and ecchymosis, and positive meningeal irritation sign. There were increases in peripheral white blood cells and neutrophils, but reductions in the hemoglobin level and platelet count in the two children. They had a significant increase in C-reactive protein. There were hundreds or thousands of white blood cells in the cerebrospinal fluid, mainly neutrophils. Increased protein contents but normal levels of glucose and chloride in the cerebrospinal fluid were found. Head CT scan showed multiple hematomas in the right cerebellum and both hemispheres in one child. Bone marrow cytology indicated infection in the bone marrow, and both blood culture and bone marrow culture showed methicillin-resistant Staphylococcus aureus (MRSA). Both patients had cardiac murmurs and progressive reductions in the hemoglobin level and platelet count during treatment, and echocardiography showed the formation of vegetation in the aortic valve. Therefore, the patients were diagnosed with infectious endocarditis (IE). Vancomycin was used as the anti-infective therapy based on the results of drug sensitivity test. One child was cured after 6 weeks, and the other child was withdrawn from the treatment and then died. Dynamic monitoring of cardiac murmurs should be performed for children with unexplained fever, and echocardiography should be performed in time to exclude IE. IE should also be considered for children with purulent meningitis and skin and mucosal bleeding which cannot be explained by the reduction in platelet count.

The surgical implications of purpura fulminans.

Purpura fulminans is an uncommon catastrophic syndrome that occurs in children, typically one to four weeks after a seemingly benign infectious process. The child usually presents with a high fever, purpuric ecchymosis, hypotension, disseminated intravascular coagulation, and gangrene of the extremities. We have recently treated six children, whose mean age was 22 months; three were male and three were female. Five of the six had a change of mental status upon initial examination. Their mean temperature was 104 degrees F. All six children had purpuric involvement of their extremities; three had involvement of their hands, two had involvement of their faces, and two had involvement of their trunks. All had absent palpable pulses and sluggish capillary refill in the involved hands and feet. Two patients died shortly after admission as a result of severe end-stage sepsis. The platelet counts in these two patients, and the white blood cell counts were markedly depressed. The mean platelet count of the survivors was 370,000 and the mean white blood cell count was 25,000. Lumbar punctures were positive for bacterial meningitis in five patients and viral meningitis in one patient. All patients were treated with intravenous heparin. Of the four survivors, two lost significant tissue and required multiple plastic reconstructive procedures, and two improved on heparin alone with no tissue loss. In addition to systemic support and intravenous antibiotics, the mainstay of treatment is one of immediate heparinization and a continuous heparin drip. Heparin prevents subsequent small vessel thrombosis and limits tissue loss due to ongoing purpura. Conservative management of the purpuric lesions is the treatment of choice until final demarcation occurs.

Cerebrospinal fluid lymphocytosis in an infant with acute Streptococcus pnuemoniae meningitis: a case report.

A 10 month-old female infant presented with one day of high fever with drowsiness and seizures. Physical examination showed meningeal irritation and mild cyanosis. The cerebrospinal fluid (CSF) profile revealed opening pressure of 27 cmH2O, closing pressure of 17 cmH2O, red blood cells 310 cells/microL, white blood cells 100 cells/microL of which 90 percents were lymphocytes, protein 391 mg/dl, sugar 0 mg/dL and blood sugar 74 mg/dl. Numerous gram positive diplococci were found on CSF Gram-stained smear. Bacterial meningitis was diagnosed and cefotaxime 300 mg/kg/day plus vancomycin 60 mg/kg/ day were given empirically. The patient developed hypotension, poor tissue perfusion, dyspnea and disseminated intravascular coagulopathy (DIC). She expired 10 hours after hospitalization. The CSF and blood culture grew out Streptococcus pneumoniae serotype 6B with the minimal inhibitory concentration (MIC) of 0.5 and 1.5 microg/mL for penicillin and cefotaxime respectively. Atypical characteristics of CSF in bacterial meningitis may cause delay in empirical antimicrobial therapy. Gram-stained smear of CSF is helpful for rapid diagnosis and proper management.

[Therapy-refractory fulminant meningococcal sepsis].

Two cases of the severe form of meningococcal infection are described. A 17-year-old girl and a (unrelated) 2-year-old boy suddenly developed fever and rigor. Several hours later petechiae of the skin were noted: they rapidly spread. On admission the girl was found to have a severe consumptive coagulopathy (prothrombin 24%, partial thromboplastin time 104 sec, fibrinogen 73 mg/dl, platelets 35,000/microliters). She died two-and-a-half hours after admission of treatment-resistant shock. The boy had at first only a low prothrombin value (39%), but later the other coagulation values also became abnormal. He died 16 hours after admission from the consumptive coagulopathy and profound anaemia (haemoglobin 7.4 g/dl, haematocrit 0.23). Neither patient had any clinical signs of meningitis. Isolation of Neisseria meningitidis from blood cultures confirmed the diagnosis.

List of MeSH codes (E01)

– cytodiagnosis – amniocentesis – biopsy – biopsy, needle – biopsy, fine-needle – chorionic villi sampling – conization – sentinel lymph node biopsy – chorionic villi sampling – cytopathogenic effect, viral – spinal puncture – vaginal smears – hematologic tests – blood cell count – erythrocyte count – reticulocyte count – leukocyte count – lymphocyte count – cd4 lymphocyte count – cd4-cd8 ratio – platelet count – blood coagulation tests – international normalized ratio – partial thromboplastin time – prothrombin time – thrombelastography – thrombin time – whole blood coagulation time – blood grouping and crossmatching – blood sedimentation – bone marrow examination – erythrocyte aggregation – erythrocyte indices – figlu test – hematocrit – hemoglobinometry – osmotic fragility – platelet function tests – bleeding time – clot retraction – platelet count – schilling test

Renal cell carcinoma

Complete blood cell count The CBC provides a quantified measure of the different cells in the whole blood sample from the patient. Such cells examined for in this test include red blood cells (erythrocytes), white blood cells (leukocytes) and platelets (thrombocytes). A common sign of renal cell carcinoma is anaemia whereby the patient exhibits deficiency in red blood cells. CBC tests are vital as a screening tool for examination the health of patient prior to surgery. Inconsistencies with platelet counts are also common amongst these cancer patients and further coagulation tests, including Erythrocyte Sedimentation Rate (ESR), Prothrombin Time (PT), Activated Partial Thromboplastin Time (APTT) should be considered.

List of MeSH codes (G09)

The source for this content is the set of 2006 MeSH Trees from the NLM. – circulatory and respiratory physiology – blood physiology – blood physiologic phenomena – acid-base equilibrium – bleeding time – blood bactericidal activity – blood cell count – erythrocyte count – reticulocyte count – leukocyte count – lymphocyte count – cd4 lymphocyte count – cd4-cd8 ratio – platelet count – blood viscosity – blood volume – erythrocyte volume – plasma volume – erythrocyte deformability – erythrocyte indices – hematocrit – osmotic fragility – partial thromboplastin time – platelet adhesiveness – prothrombin time – reticulocytosis – thrombin time – whole blood coagulation time

Cutaneous manifestations of Strongyloides stercoralis hyperinfection in an HIV-seropositive patient.

A 41-year-old human immunodeficiency virus (HIV)-positive man was hospitalized with complaints of a 4-week history of nausea and vomiting, associated with decreased oral intake, and a 4-day history of frontal headache and fever. His medical history was significant for a gunshot wound to the head 3 years prior, with a residual seizure disorder. He also had two previous hospitalizations, both for culture-negative bacterial meningitis; the first episode occurred 12 months before admission and the second episode occurred 5 months later. At that time, he was found to be positive for serum antibodies against HIV and a CD4+ T-lymphocyte count of 126/mm3. He had no known drug allergies and was not receiving any medication. On admission, the patient was febrile (104.0 degrees F) and hypotensive (blood pressure, 92/40 mm Hg). Pertinent physical examination findings included cachexia with bitemporal wasting, dry mucus membranes, adherent white patches on the oral mucosa, and negative Kernig's and Brudzinski's signs. His laboratory results revealed macrocytic anemia, a decreased serum sodium of 125 mEq/L, and a normal total leukocyte count with a CD4+ T-lymphocyte count < 50/mm3. Lumbar puncture opening pressure was elevated at 160 mm Hg, and cerebrospinal fluid analysis showed an increased white cell count of 97/microL (84% lymphocytes), a decreased glucose level of 26 mg/dL, and a decreased protein level of 42 mg/dL. The patient was started on empiric therapy that included intravenous ampicillin and cefotaxime, oral Bactrim, and clotrimazole lozenges for thrush. Cerebrospinal fluid culture was positive for Escherichia coli, sensitive to cefotaxime. Two days later, the patient developed fine, erythematous, nonblanchable macules primarily on his abdomen, with minimal involvement of his thorax and back. His skin lesions remained unchanged for the next 2 weeks. Repeat lumbar puncture was performed after 14 days of cefotaxime. The cerebrospinal fluid analysis showed an elevated white cell count of 7/microL (100% lymphocytes), a decreased glucose level of 53 mg/dL, and a decreased protein level of 33 mg/dL. The cerebrospinal fluid culture was now positive for Pseudomonas aeruginosa resistant to cefotaxime. The patient was started on imipenem. On day 34 of his admission, the patient became tachypneic with complaints of dyspnea. A chest roentgenogram revealed bilateral patchy infiltrates. He was transferred to the intensive care unit and intubated for hypoxemic respiratory failure (arterial blood gas values on 6 L of oxygen: pH, 7.46; bicarbonate, 23; and oxygen saturation, 37). That evening, the patient was also noted to have diffuse petechiae and purpura in a reticulated pattern over his abdomen (Figure 1A and 1B), most heavily concentrated in the periumbilical region, extending to the axillae and upper thighs. A 3x3-mm punch biopsy from abdominal skin demonstrated Strongyloides stercoralis larvae in the dermis (Figure 2A and 2B). His sputum specimen was teeming with adult S stercoralis worms (Figure 3) and, subsequently, numerous S stercoralis larvae were observed not only from the bronchoalveolar lavage but also from the nasogastric fluid specimen. These findings confirmed the diagnosis of disseminated strongyloidiasis. On hospital day 35, the patient was doing poorly and was started on thiabendazole (1250 mg twice daily for 28 days). Nine days later, ivermectin (4.5 mg once daily for 3 days for 2 courses) was also added. He continued to clinically deteriorate. The patient died 31 days after systemic antihelminthic treatment was initiated.

Meningococcal Meningitis -- Evaluation

Initial blood tests should include full blood cell count, electrolytes, coagulation studies, and blood cultures. [28] Lumbar puncture is necessary for a definitive diagnosis, but if clinical suspicion is high, diagnostic tests should not delay antibiotic administration.

Prognostic factors of severe infectious purpura in children.

The French Club of Pediatric Intensive Care has prospectively studied 90 cases of infectious purpura which were hospitalized in 1981; the purpose of this study was to determine prognostic factors. The statistical study (X2 test) of all these cases is in agreement with data in the literature and shows that the mortality is significantly higher when there is: shock (p less than 0.001), coma (p less than 0.05), ecchymotic or necrotic purpura (p less than 0.01), temperature less than 36 degrees C (p less than 0.05), no clinical meningism (p less than 0.001), white cell count less than 10,000/mm3 (p less than 0.05), thrombocytopenia less than 100,000 (p less than 0.01), fibrinogen less than 1.5 g/l (p less than 0.001), kalemia greater than 5 mEq/l (p less than 0.01), spinal fluid cell count less than 20/mm3 (p less than 0.01). Because shock is one of the main prognostic factors (23 deaths in 55 shocked patients, versus 2 in 35 non-shocked) we have performed another statistical study (with the Benzecri method) to determine a prognostic index for patients in shock. For its determination, five initial parameters are used: age, kalemia, white cell count, clinical meningism, platelet count. The predictive value for survival is 91%. The predictive value for death is 87%. The score was applied on the patients hospitalized in shock in 1982: the predictive value for survival is 75%, the predictive value for death is 61%.

Asplenia

In an emergency room or hospital setting, appropriate evaluation and treatment for an asplenic febrile patient should include a complete blood count with differential, blood culture with Gram stain, arterial blood gas analysis, chest x-ray, and consideration for lumbar puncture with CSF studies. None of these evaluations should delay the initiation of appropriate broad-spectrum intravenous antibiotics. The Surviving Sepsis Campaign guidelines state that antibiotics should be administered to a patient suspected of sepsis within 1 hour of presentation. Delay in starting antibiotics for any reason is associated with a poor outcome.

Meningococcal disease

Signs and symptoms Meningitis The patient with meningococcal meningitis typically presents with high fever, nuchal rigidity (stiff neck), Kernig's sign, severe headache, vomiting, purpura, photophobia, and sometimes chills, altered mental status, or seizures. Diarrhea or respiratory symptoms are less common. Petechiae are often also present, but do not always occur, so their absence should not be used against the diagnosis of meningococcal disease. Anyone with symptoms of meningococcal meningitis should receive intravenous antibiotics before the results of lumbar puncture, as delay in treatment worsens the prognosis.

One-month-old boy with group B streptococcal meningitis, subdural effusion, and high levels of interleukin-6.

Meningitis is associated with elevated levels of inflammatory cytokines in the blood, cerebrospinal fluid (CSF), and subdural fluid. Subdural effusion prolongs fever in patients with meningitis. However, the reason for this remains unclear. A healthy one-month-old boy was admitted after presenting with bacterial meningitis. He was administered meropenem, cefotaxime, and dexamethasone intravenously. On the 3rd day, blood and CSF cultures revealed the presence of Group B Streptococcus from samples collected on day 1. Subsequently, ampicillin and gentamicin replaced the previous combination of antimicrobials used. On the 4th day, brain magnetic resonance imaging with contrast showed bilateral cerebral ventriculitis and left subdural effusion. On the 11th day, since the subdural effusion had worsened, we performed a subdural puncture from the anterior fontanelle. Owing to the prolonged fever, he was intravenously injected immunoglobulin on day 13. He was afebrile on day 23. Antimicrobials were administered for 28 days. Levels of interleukin-6 (IL-6) in the serum and CSF were the highest on the 1st day at 20,600 pg/mL and 170,000 pg/mL, respectively, and decreased upon treatment. IL-6 concentration in the subdural fluid (30,000 pg/mL) was much higher than that in the serum (9 pg/mL) and CSF (2600 pg/mL). To the best of our knowledge, this is the first report on the cytokines in subdural fluid in patients with group B Streptococcal meningitis. Subdural effusion maintained high levels of IL-6 even after the levels in the blood and CSF decreased dramatically. This could explain why subdural effusion prolongs fever in patients with meningitis.

Acute meningococcal meningitis: analysis of features of the disease according to the age of 255 patients. Copenhagen Meningitis Study Group.

Clinical and laboratory features of acute meningococcal meningitis according to age were studied in 255 patients. Whereas males accounted for three out of five patients aged 0-4 years, females accounted for three out of four patients older than 50 years of age. All patients had clinical signs of nuchal rigidity and fever. Patients older than 30 years of age had less frequent petechiae (62%) than younger patients (81%). Furthermore, elderly patients above 50 years of age were prone to an obtunded mental state and a prolonged disease course with fever. Without relation to age, 2/3 had purulent meningitis and 2/3 had marked peripheral leucocytosis (> 15 x 10(9) cells/l); 90% of patients had at least one of these findings. The cellular inflammatory response in peripheral blood indicated a bacterial aetiology in > 95% of the cases. More than 80% of children and adults had abnormal CSF biochemical findings, but the level of protein and the glucose ratio (CSF/serum) were positively and negatively correlated to increasing age of the patient, respectively: thus, in children these biochemical markers may be unreliable in the differentiation between a bacterial and non-bacterial aetiology. Thrombocytopenia (< 100.000 x 10(9)/I) was not associated with age, though the lowest platelet count was found in elderly patients. The case fatality rate was 7.5%, but neither age, sex nor sign of septicaemia was associated with fatality. Thrombocytopenia, a lowered coagulation index (< 0.5, factors II, VII, X), a moderate anaemia (haemoglobin < 11 g/dl), an obtunded mental state and a history of convulsions were poor prognostic factors; only anaemia was independently correlated to fatality so this should be considered as an important prognostic marker in the acute phase of meningococcal meningitis.

Prediction of bacterial meningitis in children with meningeal signs: reduction of lumbar punctures.

Physicians often have to perform a lumbar puncture to ascertain the diagnosis in patients with meningeal signs, because of the serious consequences of missing bacterial meningitis. The aim of this study was to derive and validate a clinical rule to predict bacterial meningitis in children with meningeal signs, to guide decisions on the performance of lumbar punctures. Information was collected from records of patients (aged 1 mo to 15 y) consulting the emergency department of the Sophia Children's Hospital between 1988 and 1998 with meningeal signs. Bacterial meningitis was defined as cerebrospinal fluid (CSF) leucocyte count >5 cells microl(-1) with a positive bacterial culture of CSF or blood. The diagnostic value of predictors was judged using multivariate logistic modelling and area under the receiver operating characteristic curves (ROC area). In the derivation set (286 patients, years 1988-1995) the duration of the main complaint, vomiting, meningeal irritation, cyanosis, petechiae and disturbed consciousness were independent clinical predictors of bacterial meningitis. The ROC area of this model was 0.92. The only independent predictor from subsequent laboratory tests was the serum C-reactive protein concentration, increasing the ROC area to 0.95. Without missing a single case, this final model identified 99 patients (35%) without bacterial meningitis. Validation on 74 consecutive patients in 3 subsequent years (1996-1998) yielded similar results. This prediction rule identifies about 35% of the patients with meningeal signs in whom a lumbar puncture can be withheld without missing a single case of bacterial meningitis. For the individual patient this prediction rule is valuable in deciding whether or not to perform a lumbar puncture.

Diagnosis of hemorrhagic diseases; evaluation of procedures. II. Preoperative tests.

Routine preoperative tests such as the determination of bleeding time and coagulation time are unnecessary and are not recommended. Rulings which require routine preoperative tests result in the adoption of inferior and unreliable time-saving methods in the laboratory. If the clinical staff insists that laboratory procedures to predict hemorrhage be performed on every patient scheduled for operation, approved methods of performing the tests should be employed. Preoperative procedures should include a personal and a family history, a careful and complete physical examination and screening laboratory tests such as urinalysis, hematocrit, leukocyte count and smear examination, including estimation of the number of thrombocytes. Special hemorrhagic studies are indicated on selected patients. These selected patients include those who have a history of abnormal bleeding, those who consider themselves "easy bleeders" or who have apprehension concerning hemorrhage at the time of operation, and those who have physical signs of hemorrhage. Special hemorrhagic studies should also be performed on patients who have diseases that are known to be associated with vascular and coagulation abnormalities, infants who have not been subjected to tests of trauma and on patients from whom a reliable history cannot be obtained. Extra precaution should be taken if operation is to be performed in hospitals or clinics that do not have adequate blood banking facilities and if the operation to be performed is one in which difficulty in hemostasis is anticipated. THE PREOPERATIVE TESTS THAT ARE INDICATED ON SELECTED PATIENTS SHOULD INCLUDE AS A MINIMUM: The thrombocyte count, determination of the bleeding time by the Ivy method, determination of the coagulation time by the multiple tube method and the observation of the clot. Where facilities are available, the hemorrhagic study should also include the plasma and serum prothrombin activity tests.

Dog health

Mouse and rat poison, hypercalcemia type Mouse and rat poisons containing cholecalciferol cause hypercalcemia and hyperphosphatemia in dogs. Clinical signs include depression, loss of appetite, vomiting blood, weakness, and shock. Treatment is as above for recent exposure. When hypercalcemia occurs (which can take 1 to 2 weeks), treatment is with intravenous fluids (saline), diuretics, corticosteroids, and calcitonin. Long term prognosis is good once the dog is stabilized. Snail bait, metaldehyde type Ingestion can cause anxiety, muscle twitching, seizures, rapid heart rate, dilated pupils, hypersalivation, vomiting, diarrhea, and high fever due to the metaldehyde present. Treatment involves gastric lavage, intravenous fluid administration, and/or administration of activated charcoal.

[Diagnostic usefulness and predictive value of laboratory tests in disseminated vascular coagulation].

The laboratory tests of 38 patients in pediatric age with Disseminated Intravascular Coagulation (DIC) were retrospectively evaluated. In all patients were performed PT, aPTT, platelets count, FDP dosage and biological assay of Fibrinogen. In most of them the activity of FII, FV, FVII, FX and FVIII was assaied. According to the diagnostic criteria of FSP greater than 8 micrograms/ml, Platelets less than 150 10(9)/1 and Fibrinogen less than 150 ml/dl, in 16 patients the diagnosis of DIC was possible since first examination, while in 9 patients it became possible within 2-4 days; in 13 patients we never could diagnose DIC, although it was reasonably present, since the criteria above mentioned were never simultaneously satisfied. Looking back in our experience, we confirm that the platelets count and the quantitation of plasmatic Fibrin Degradation Products (FDP) are the most useful tests for the diagnosis of full blown DIC, and that the biological assay of plasmatic fibrinogen helps to follow the disorder. A low level of FVIII:C seems to be a forecast of failure. None of the other test performed give any useful information for diagnosis when it is not possible with the above mentioned tests.

Deep vein thrombosis

In arterial thrombosis, blood vessel wall damage is required, as it initiates coagulation, but clotting in the veins mostly occurs without any such mechanical damage. The beginning of venous thrombosis is thought to arise from "activation of endothelial cells, platelets, and leukocytes, with initiation of inflammation and formation of microparticles that trigger the coagulation system" via tissue factor. Vein wall inflammation is likely the inciting event. Importantly, the activated endothelium of veins interacts with circulating white blood cells (leukocytes). While leukocytes normally help prevent blood from clotting (as does normal endothelium), upon stimulation, leukocytes facilitate clotting. Neutrophils are recruited early in the process of venous thrombi formation. They release pro-coagulant granules and neutrophil extracellular traps (NETs) or their components, which play a role in venous thrombi formation. NET components are pro-thrombotic through both the intrinsic and

[Changes in erythrocyte structure and in platelets in elderly patients with disseminated intravascular coagulation].

We measured the platelet distribution width, the mean platelet volume, the volume percentage of platelets, and the platelet-to-large-cell ratio in 15 elderly patients with disseminated intravascular coagulation (DIC). Peripheral venous blood mixed with ehtylenediaminetetraacetic acid was analyzed with a Sysmex E-4000 analyzer. The underlying diseases were sepsis, pneumonia, pyelonephritis, and other inflammatory diseases. The mean duration of survival from the onset of DIC was 16.9 +/- 23.9 days. The distribution of red cell sizes before the onset of DIC did not differ significantly from that in patients without DIC, but fragmentation of erythrocytes on blood films was more common in the early stage of DIC (p < 0.01). Before the onset of DIC, the two groups did not differ significantly in the frequency of giant platelets on blood smears. At the onset of DIC, the platelet distribution width, the mean platelet volume, and the platelet-to-large-cell ratio were significantly higher than in patients without DIC. The concentration of glutamic-oxaloacetic transaminase and those of other serum enzymes did not change significantly, but the serum creatinine concentration and the blood urea nitrogen level increased as the platelet-to-large-cell ratio increased. No significant relation was evident between the levels of serum C-reactive protein and creatinine, between the platelet-to-large-cell ratio and the mean volume of red blood cells, or between the platelet-to-large-cell ratio and the distribution of red cell sizes. These data suggest that studies of platelets are more useful in the diagnosis of DIC at early stages of impaired organ function than are other indicators of inflammation such as the level of C-reactive protein.

Laboratory tests in evaluation of acute febrile illness in pediatric emergency room patients.

The rising costs of health care and the movement for health care reform have focused attention on methods of cost containment. Of routine laboratory and radiologic procedures, complete blood cell count (CBC) and determination of serum electrolyte values rank as high as 2nd and 9th in overall cost. We retrospectively studied use of the clinical laboratory to aid diagnosis of an acute infectious event in a pediatric emergency department population. For 5 months, we reviewed medical records of pediatric patients younger than 15 years brought to the emergency department because of a febrile episode. Of 155 cases reviewed, electrolyte concentrations were determined in 108 patients and CBC in 155. In all patients, either culture or rapid test for streptococcal organisms was performed. In addition, 838 pediatric patients with similar symptoms but who did not undergo laboratory testing were monitored for 100 days. Measures of effectiveness including sensitivity, specificity, positive and negative predictive values, and likelihood ratio were used to correlate specific laboratory findings with antibiotic therapy, serious bacterial disease, and culture positivity. Electrolyte abnormalities were found largely to be dismissed clinically, with the major clinical response consisting of parental education about hydration. The CBC profile was evaluated, with white blood cell count (WBC) indicator limits of > 10,000, > 10,000 but < 15,000, and > 15,000/mm3, and differentiated into absolute neutrophil count, neutrophil percent, and band cell percent. Temperature was evaluated as an independent variable. Insofar as serious bacterial disease and culture positivity, sensitivity was uniformly low (70%), and specificity was only marginably acceptable for WBC > 15,000 (77%). Both positive predictive values and likelihood ratio were low with respect to predicting either serious bacterial disease or culture positivity, emphasizing the limited usefulness of these clinical laboratory measurements. The best hematologic predictors of serious bacterial disease or culture positivity were obtained with automated hematologic analyzers and exceeded manual differential measurement of neutrophil percent and band cell percent. In addition, we correlated the administration of antibiotics with the various hematologic parameters and discovered that WBC > 15,000, regardless of cause, almost uniformly resulted in treatment (positive predictive value, 93.5%; likelihood ratio, 5.60). These findings support the use of automated hematology analyzer-derived measurements and question the use of manual differential counts, unless specific issues are to be addressed. Furthermore, the findings seem to support more reliance on clinical impression and less on laboratory values.

[Recurrent hematomas and normal standard hemostasis tests].

The authors report the case of a 22-month-old boy experiencing a voluminous subcutaneous haematoma, 72 hours after a head trauma. Two subsequent drainages of this haematoma were required because of its recurrence. The child, whose parents had blood relations, suffered from recurrent bleeding since his birth. A standard haemostasis assessment including prothrombin time, activated partial thrombopiastin time, bleeding time, concentration of fibrinogen and platelet count was unremarkable. Therefore, coagulation factors were explored. An inherited factor XIII deficiency (less than 2%) was recognized. A new drain was inserted, after administration of factor XIII concentrate. The time course of the haematoma was favourable. After discharge, the prophylactic therapy consisted of an injection of factor XIII concentrate (50 Ul.kg-1) every 5 weeks.

Lumbar puncture

Cell count The presence of white blood cells in cerebrospinal fluid is called pleocytosis. A small number of monocytes can be normal; the presence of granulocytes is always an abnormal finding. A large number of granulocytes often heralds bacterial meningitis. White cells can also indicate reaction to repeated lumbar punctures, reactions to prior injections of medicines or dyes, central nervous system hemorrhage, leukemia, recent epileptic seizure, or a metastatic tumor. When peripheral blood contaminates the withdrawn CSF, a common procedural complication, white blood cells will be present along with erythrocytes, and their ratio will be the same as that in the peripheral blood.

An outbreak of an infection associated with circulating activated monocytes and hemophagocytes in children in Bombay, India.

From May 1985 to December 1989, while doing blood counts on hospitalized children in Bombay, over 300 blood smears showed an impressive number of activated monocytes (AMs) and hemophagocytes (HPs). Many AMs resembled macrophages. The AM-HPs were visible in blood for 1-10 days, accompanied by a neutrophilia and a marked thrombocytopenia. Clinical features associated with these smears were fever, unresponsiveness to antibiotics, symptoms referable to the CNS and respiratory and/or gastrointestinal tracts, and bleeding. Ninety percent of affected children were under 2 years of age. The illness resolved completely or was fatal in 30%, with bleeding or respiratory failure, within 2 weeks. Children older than 2 years had underlying illness and high fever, and 40% died. Surgical candidates had obstructive gastrointestinal pathologic findings, from the stomach to the ileum. Babies under 1 month of age died, with clinical signs of deterioration and bleeding. Bone marrows were unremarkable. Few or no AM-HPs were seen. The fibrin split product tests were positive. Liver function test results were normal. Autopsies on six cases revealed edema and bleeding or thrombosis in the lungs, brain, and gastrointestinal tract. Only one neonate had a mild histiocytic infiltration in the lungs and liver. Features in common with and differences from virus-associated hemophagocytic syndromes are discussed.

Neonatal sepsis

Diagnosis Neonatal sepsis screening: DLC (differential leukocyte count) showing increased numbers of polymorphs. DLC: band cells > 20%. increased haptoglobins. micro ESR (erythrocyte sedimentation rate) titer > 15mm. gastric aspirate showing > 5 polymorphs per high power field. newborn CSF (cerebrospinal fluid) screen: showing increased cells and proteins. suggestive history of chorioamnionitis, PROM (premature rupture of membranes), etc... Culturing for microorganisms from a sample of CSF, blood or urine, is the gold standard test for definitive diagnosis of neonatal sepsis. This can give false negatives due to the low sensitivity of culture methods and because of concomitant antibiotic therapy. Lumbar punctures should be done when possible as 10-15% presenting with sepsis also have meningitis, which warrants an antibiotic with a high CSF penetration. CRP is not very accurate in picking up cases.

[An elderly case of thrombotic thrombocytopenic purpura].

A 78-year-old woman was admitted to our hospital because of disorientation and fever on January 21, 1992. Two days before admission she experienced vomiting, anorexia and general malaise. Laboratory examinations on admission disclosed a hemoglobin level of 11.1 g/dl and a platelet count of 8,000/microliters. The peripheral blood smear revealed anisocytosis with numerous schistocytes and poikilocytes. Polychromatophilic and nucleated red blood cells were also seen, and the reticulocyte count was 38/1000. Her serum lactate dehydrogenase (LDH) value was 2,977 WU and the total serum bilirubin level was 3.5 mg/dl with 2.7 mg/dl indirect reacting fraction. Serum creatinine was 4.7 mg/dl. Her consciousness became semicomatose after a systemic seizure which lasted approximately 15 seconds and her hemoglobin level decreased to 8.5 g/dl on hospital day 2. Therefore, we diagnosed her as having thrombotic thrombocytopenic purpura (TTP) because of the presence of all 5 features, that is, thrombocytopenia, microangiopathic hemolytic anemia, fluctuating neurologic abnormalities, renal dysfunction and fever. A plasmapheresis with fresh frozen plasma (FFP) replacement was begun on that day. She was also treated with anti-platelet agents, 80 mg/day aspirin, and 300 mg/day dipyridamole. Moreover, packed red blood cells (PRC) were infused. While also receiving diphenylhydantoin and phenobarbital to prevent convulsions, status epilepticus developed on day 3. Because of inhibited spontaneous respiration which was an adverse effect derived from diazepam and sodium thiamylal administered intravenously to treat the status epilepticus, an artificial respiration was initiated.(ABSTRACT TRUNCATED AT 250 WORDS)

A Case of Trimethoprim-Sulfamethoxazole-Induced Aseptic Meningitis Masquerading as Septic Shock.

Trimethoprim-sulfamethoxazole-induced aseptic meningitis (TSIAM) is a rare adverse reaction to a commonly prescribed antibiotic. We describe a case of severe TSIAM which resembled septic shock. A 30-year-old male with relapsed Hodgkin's lymphoma 25 days status post autologous stem cell transplant presented to our clinic for evaluation of trimethoprim-sulfamethoxazole (TMP-SMX) hypersensitivity. After review of patient's history and records, we had a low suspicion for a TMP-SMX adverse reaction and conducted an oral challenge to one 160 mg/800 mg tab of TMP-SMX. Four hours later, the patient developed vomiting, lightheadedness, and disorientation with progression to rigors, fever, tachycardia, and hypotension. He was admitted for fluid resuscitation and broad-spectrum antibiotic coverage for neutropenic fever and possible septic shock. A lumbar puncture performed due to complaints of headache, photophobia, and neck pain showed 375 white blood cells/µL with 73% neutrophil predominance, normal glucose (75 mg/dL), and elevated protein (101 mg/dL); additional cerebrospinal fluid (CSF) studies were negative for infectious etiologies. Fever and headache resolved by hospital day 4, at which time patient was discharged home. We believe this case represents TSIAM given the characteristic timing of symptom onset, CSF findings, and timing of symptom resolution without other clear etiology found on extensive infectious evaluation. It is important for allergists to recognize TSIAM, including its potential presentation as shock, in order to appropriately diagnose and counsel patients who seek evaluation for TMP-SMX adverse reactions.

Disseminated intravascular coagulation in a case of brucellosis.

Brucellosis is a multisystem disease with a broad spectrum of clinical manifestations; hematological abnormalities ranging from fulminant as of disseminated intravascular coagulation (DIC) to anaemia, leucopoenia, thrombocytopenia, and clotting disorders. In this report, we present DIC in a case of brucellosis because of rare presentation. A 3-year-old boy was admitted with the complaints of continuous fever, vomiting, abdominal pain, and bruise on leg. He looked pale and his physical examination revealed purpuric skin lesions on both legs. A mild hepatosplenomegaly was noted on palpation. Laboratory tests showed hematocrit 21%, hemoglobin 7 g/dL, platelet count 20,000/mm(3), prothrombin time 19 seconds, activated partial thromboplastin time 48 seconds, plasma fibrinogen level 20 mg/dL, and D-dimer 8 µg/mL. Serum antibrucella titration agglutination test was found to be 1 of 1280 positive. Blood cultures performed on specimens obtained at the time of admission yielded Brucella melitensis. The clinical and laboratory findings were consistent with DIC.

[Meningitis caused by Streptococcus suis type 2 in an adult].

A 54-year-old huntsman who 3 days previously had shot a wild pig, developed severe headache, nausea and vomiting over the last 10 hours. Physical examination was unremarkable except for an 8 x 4 cm large reddening of the skin over the right tibia and fever (38.2 degrees C). Cranial computed tomography was normal. Cerebrospinal fluid showed pleocytosis (5.200 cells/mm3). Gram-stained (CSF) smear showed gram-positive cocci and an increased white cell count (14,000/microliters) was found in blood. After the diagnosis of bacterial meningitis had been made antibiotics were given intravenously (penicillin G 10 mill. IU, three times daily on days 1 to 16: at first with cefotaxim, three times daily 2 g on days 1 to 3, then with gentamicin twice 80 mg on days 3 to 13). The acute neurological signs quickly regressed, the pretibial reddening (presumably at the port of entry) disappeared, as did the fever on the 4th day of the illness. The streptococci isolated from CSF and blood were identified as 5. suis type 2 (Lancefield group R). But despite the early and effective antibiotic treatment cochleovestibular symptoms (hearing impairment, vertigo and unsteady gait) set in after initial improvement, a frequent complication of S. suis meningitis. S. suis should be considered as the causative organism of generalized septicaemia and meningitis in adults, if the history reveals contact with domestic or wild pigs and there are early cochleovestibular signs.

[Early indicators of dengue infection in children].

To identify clinical manifestations and laboratory findings useful for the early diagnosis of dengue in children. We prospectively evaluated 125 children (aged 5 to 12 years old) with acute febrile syndrome with no apparent etiology. Paired serologic tests and/or viral culture were performed and dengue infection was confirmed in 40 patients and ruled out in 68 (17 indefinite cases). Early clinical manifestations (within the first 4 days of the disease) in the groups with dengue and other causes of febrile syndrome were compared. Independent indicators of dengue were determined in a multivariate logistic regression analysis. When clinical manifestations and complete blood count were considered, the independent indicators of dengue were: absence of nasal discharge, facial flushing, and leukocyte count < or = 4,500/.l. With at least two of these findings, a sensitivity of 67 % and a specificity of 72 % for the diagnosis of dengue were obtained. When coagulation tests were considered, a model for diagnosis was composed of: absence of nasal discharge, leukocyte count < or = 4500/.l, prothrombin time > 14 seconds, and partial thromboplastin time > 29 seconds. Two of these findings suggested a diagnosis of dengue with a sensitivity of 90 % and a specificity of 52.9 %. With at least 3 findings, specificity increased to 89.7 % and sensitivity decreased to 50 %. The presence of the four components of this latter model shows a specificity of 100 %. Some clinical manifestations and simple laboratory tests could aid the early detection of dengue infection in children.