Stepwise Diagnostic Approach Research Articles

Recommendations for the diagnosis of paroxysmal nocturnal hemoglobinuria: a German-Austrian Consensus1)

Abstract Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, life-threatening hematological disease. An acquired mutation in the PIG-A gene in hematopoietic precursor cells leads to a deficiency of glycosylphosphatidylinositol (GPI), a common membrane anchor for certain cell surface proteins. The consequence is a deficiency of the decay-accelerating factor (recognized by antibodies of the cluster CD55) and of the membrane inhibitor of reactive lysis (MIRL, recognized by CD59 antibodies) on the surface of blood cells leading to dysregulation of the complement cascade resulting in characteristic intravascular hemolysis and thromboembolic complications. The analysis of GPI-anchored proteins on blood cells is the recognized diagnostic gold standard. Some aspects of the recently published international guidelines are still a matter of discussion. On the basis of these guidelines, we discussed practical recommendations, which led to the German-Austrian consensus paper presented here. It contains specific proposals for indication of the test, preanalytical aspects, how to perform immunophenotyping, and for result interpretation. We propose a two-step diagnostic approach. Step 1 is a screening and step 2 is a confirmation of the diagnosis. The latter should be restricted to expert laboratories’ experience with PNH. According to this algorithm for a stepwise diagnostic approach, we recommend which antibody panel should be used in which step. The most frequent sources of error and how to avoid them are also summarized. This consensus should support medical laboratories to make an early and correct diagnosis of what is important to therapy and prognosis of the patient. Aspects of economic efficiency and feasibility were also included in our considerations.

Cushing′s syndrome: Stepwise approach to diagnosis

The projected prevalence of Cushing's syndrome (CS) inclusive of subclinical cases in the adult population ranges from 0.2–2% and it may no longer be considered as an orphan disease (2–3 cases/million/year). The recognition of CS by physicians is important for early diagnosis and treatment. Late-night salivary cortisol, dexamethasone suppressiontesti, or 24-h urine free cortisol are good screening tests. Positively screened cases need stepwise evaluation by an endocrinologist. This paper discusses the importance of screening for CS and suggests a stepwise diagnostic approach to a case of suspected hypercortisolism.

Proposition of a Stepwise Diagnosis Method for a Cracked Beam using a Force Identification Approach

Machine condition monitoring and diagnosis have become increasingly important, and the application of these processes to stationary structures and rotating machinery has been widely investigated. The authors previously proposed a stepwise diagnosis method. In that method, the location of the abnormality is first estimated using the force identification approach, and then the cause and the severity of the abnormality are identified. But the method was applicable for an abnormality of linear property. In this study, a stepwise diagnostic approach for a beam with an abnormality of nonlinear property, that is, a breathing crack, is proposed. In this method, the location and the severity of abnormality are identified by using the multi-frequencies of response under the abnormal condition. Using the numerical example of a uniform beam fixed at both ends, we confirmed the validity of the method and determined that the selection of the excitation frequency was very important. Moreover, we showed the applicability of the method by using experimental data. We conclude that the proposed diagnosis method is feasible for identifying the abnormality of a breathing crack.

Approach to mental retardation and global developmental delay.

ObjectiveRetardation (MR) or Intellectual Disability is one of three chronic and disabling neurological disorders of children and adolescents. Its prevalence is estimated 1-3% of the population. MR is defined as significant sub-average intellectual functioning and adaptive behavior that become detectable before the age of 18. MR may come into view before 5 years as delay in at least two developmental domains which is called Global Developmental Delay (GDD). The causes of mental retardation can be considered under the titles of prenatal, perinatal and postnatal factors. Prenatal causes account for approximately 60 -80 % of the etiological factors. All patients with GDD / MR should undergo a stepwise diagnostic approach, because a specific diagnosis leads to opportunity for treatment, future planning and genetic counseling. History, physical examination and neurodevelopmental examinations are the most important parts of the approach. Recent advances in cytogenetic investigations and neuroimaging studies have led to recognition of new disorders and improvement of the diagnostic yield.

Otitis Media in Children with Congenital Immunodeficiencies

Otitis media represents one of the most common infections in childhood. Within the first 3 years of life, up to 80% of children experience at least one episode of otitis media. It is often resolved with supportive therapies and consequently not considered a worrisome problem. However, it may be an early manifestation of a severe underlying disease. Primary immunodeficiencies are rare congenital defects of the immune system that often remain unrecognized, or diagnosis can be delayed, sometimes resulting in fatal consequences for the child. Patients suffer from recurrent, prolonged, and/or unusual infections leading to local sequelae, failure to thrive, developmental delays, and systemic infections with severe courses. This review provides a brief insight into primary immunodeficiencies and an overview of leading findings that should result in further evaluation of the immune system in cases of otitis media. A stepwise diagnostic approach is proposed to facilitate early and accurate diagnosis and, consequently, effective and timely therapy to improve the patient's outcome and quality of life.

Evaluation of an open access echocardiography service in the Netherlands: a mixed methods study of indications, outcomes, patient management and trends

BackgroundIn our region (Eastern South Limburg, The Netherlands) an open access echocardiography service started in 2002. It was the first service of this kind in The Netherlands. Our study aims were: (1) to evaluate demand for the service, participation, indications, echocardiography outcomes, and management by the general practitioner (GP); (2) to analyse changes in indications and outcomes over the years.Methods(1) Data from GP request forms, echocardiography reports and a retrospective GP questionnaire on management (response rate 83%) of 625 consecutive patients (Dec. 2002 - March 2007) were analysed cross-sectionally. (2) For the analysis of changes over the years, data from GP request forms and echocardiography reports of the first and last 250 patients that visited the service between Dec. 2002 and Feb. 2008 (n = 1001) were compared.ResultsThe echocardiography service was used by 81% of the regional GPs. On average, a GP referred one patient per year to the service. Intended indications for the service were dyspnoea (32%), cardiac murmur (59%), and peripheral oedema (17%). Of the other indications (22%), one-third was for evaluation of suspected left ventricular hypertrophy (LVH). Expected outcomes were left ventricular dysfunction (LVD) (43%, predominantly diastolic) and valve disease (25%). We also found a high proportion of LVH (50%). Only 24% of all echocardiograms showed no relevant disease. The GP followed the cardiologist's advice to refer the patient for further evaluation in 71%. In recent patients, more echocardiography requests were done for 'cardiac murmur' and 'other' indications, but less for 'dyspnoea'. The proportions of patients with LVD, LVH and valve disease decreased and the proportion of patients with no relevant disease increased. The number of advices by the cardiologists increased.ConclusionOverall, GPs used the open access echocardiography service efficiently (i.e. with a high chance of finding relevant pathology), but efficiency decreased slightly over the years. To meet the needs of the GPs, indications might be widened with 'suspicion LVH'. Further specification of the indications for open access echocardiography - by defining a stepwise diagnostic approach including ECG and (NT-pro)BNP - might improve the service.

Treatment algorithms in refractory partial epilepsy

An algorithm is a "step-by-step procedure for solving a problem or accomplishing some end....in a finite number of steps." (Merriam-Webster, 2009). Medical algorithms are decision trees to help with diagnostic and therapeutic decisions. For the treatment of epilepsy there is no generally accepted treatment algorithm, as individual epilepsy centers follow different diagnostic and therapeutic guidelines. This article presents two algorithms to guide decisions in the treatment of refractory partial epilepsy. The treatment algorithm describes a stepwise diagnostic and therapeutic approach to intractable medial temporal and neocortical epilepsy. The surgical algorithm guides decisions in the surgical treatment of neocortical epilepsy.

The Approach to the Adult with Newly Diagnosed Adrenal Insufficiency

Adrenal insufficiency, primarily presenting as an adrenal crisis, is a life-threatening emergency and requires prompt therapeutic management including fluid resuscitation and stress dose hydrocortisone administration. Primary adrenal insufficiency is most frequently caused by autoimmune adrenalitis, and hypothalamic-pituitary tumors represent the most frequent cause of secondary adrenal insufficiency. However, the exact underlying diagnosis needs to be confirmed by a stepwise diagnostic approach, with an open eye for other differential diagnostic possibilities. Chronic replacement therapy with glucocorticoids and, in primary adrenal insufficiency, mineralocorticoids requires careful monitoring. However, current replacement strategies still require optimization as evidenced by recent studies demonstrating significantly impaired subjective health status and increased mortality in patients with primary and secondary adrenal insufficiency. Future studies will have to explore the potential of dehydroepiandrosterone replacement and modified delayed-release hydrocortisone to improve the prospects of patients with adrenal insufficiency.

Automated blood cell differential: State of the art and eye to the future1

Abstract Complete blood count including automated blood cell differential is one of the most frequent tests in the medical laboratory. How reliable is the method representing a diagnostic sieve in a stepwise diagnostic approach? Which pathologic conditions will be overlooked? Which body fluids can be investigated? What are the preanalytical requirements? When is a microscopic review required? Reimbursement has reached a level where a personal review of the diagram of cell clusters and of the blood film cannot be afforded. As the technology of blood cell analyzers has recently been described in this journal, this article focuses on the strengths and weaknesses of the automated blood cell differential. This allows judgment of the risks of a stepwise approach dependent on the medical discipline sending the sample.

The patient with slightly elevated pancreatic enzymes and abdominal complaints

Abdominal complaints in combination with slightly elevated serum pancreatic enzymes represent a classical clinical challenge. These symptoms may be due to coincidental unrelated harmless disorders, benign pancreatic alterations which are fairly easily treatable such as mild acute pancreatitis or uncomplicated chronic pancreatitis. However, serious, often insidious diseases such as pancreatic tumours may also present with this constellation as their first signs. Diagnostic procedures need to be stratified according to acuteness and severity of symptoms. While patients with acute onset of symptoms and severe complaints need immediate and combined laboratory and imaging investigations to allow adequate therapy, chronic and mild complaints usually justify a stepwise diagnostic approach consecutively using abdominal ultrasound, CT/MRI and endoscopic ultrasound as imaging procedures and reserving ERCP for cases which remain unclear or in which interventional therapy is needed. Diagnosis and follow-up are often particularly demanding in patients with cystic tumours of the pancreas. In chronic pancreatitis patients pain therapy and adequate control of pancreatic exocrine insufficiency may pose major problems. Patients with refractory pain may ultimately require surgical intervention. Another important indication for surgery in chronic pancreatitis is suspicion of cancer that cannot be ruled out by dedicated diagnostic procedures. This also applies to cystic tumours of the pancreas, which have a high risk of malignant transformation or may even already represent pancreatic cancer at the time of diagnosis.

Adrenal Gland Scintigraphy

There is no question that high-resolution imaging techniques have revolutionized the approach to diagnostic imaging. Computed tomography (CT) and magnetic resonance imaging provide exquisite images of the adrenal glands and offer the best initial imaging approach in the evaluation of patients with suspected adrenal disease. However, an assessment of anatomy is only a portion of the diagnostic effort, which begins with a biochemical evaluation to establish the presence of adrenal gland dysfunction. With a confirmed biochemical diagnosis in hand, a logical and stepwise diagnostic approach can be tailored to a particular patient. Where scintigraphy fits in the evaluation of diseases of the adrenal cortex and medulla in the context of high-resolution imaging and which radiopharmaceuticals should be deployed has changed substantially during the last 2 decades. Adrenal functional imaging has evolved from classic planar scintigraphy to single-photon emission computed tomography (SPECT) and positron emission tomography (PET) using tracers that, by targeting specific metabolic or synthetic processes within the gland, have depicted adrenal pathophysiology. New PET/CT and SPECT/CT technologies integrate anatomic and functional information and redefine the radiotracer principle in the larger context of high resolution anatomic imaging.

Inappropriate Sinus Tachycardia, Postural Orthostatic Tachycardia Syndrome, and Overlapping Syndromes

Inappropriate sinus tachycardia (IAST) and postural orthostatic tachycardia syndrome (POTS) are syndrome complexes with some distinctive features, overlapping clinical manifestations, and potential common mechanisms. Pathogenesis of these overlapping syndromes is poorly understood. Diagnostic and therapeutic approaches have not been standardized. This article provides an overview of the definition, clinical presentation, and proposed mechanisms of IAST and other overlapping syndromes. A stepwise diagnostic approach is suggested. A multidisciplinary management scheme is outlined. A MEDLINE search for English-language articles on IAST, POTS, and chronic orthostatic intolerance published up to 2005 was performed. Published data incorporated with our clinical experience were synthesized and presented in this review. The population of IAST is heterogeneous and underlying mechanisms are complex and likely multifactorial. Evidence suggests that both cardiac and extracardiac causes are plausible. Regional and limited autonomic neuropathies, at least in part, can provide a mechanism-based explanation of the cardiovascular indices and clinical symptoms in a significant number of patients with IAST. The regional abnormalities can be detected by autonomic testing. Among patients with IAST and evidence of autonomic dysregulation, an integrated autonomic, cardiovascular, and psychiatric management approach appears to be logical and rational when appropriate. Sinus node ablation could be considered in patients with persistent IAST in the absence of autonomic neuropathy and multisystem symptoms. Data from long-term outcomes are lacking. The current understanding of IAST mechanisms is incomplete and management approach is not adequate. Significant effort needed in clinical research to improve therapeutic outcome.

Diagnostic algorithm and management of immune-mediated complications associated with subcutaneous insulin therapy.

Immune mediated complications associated with subcutaneous insulin therapy such as insulin neutralizing antibodies and/or skin reactions are rare conditions since human insulin is in general use. Nevertheless, if it occurs, a stepwise diagnostic approach is essential for differential diagnosis and consecutive treatment of these complications. Here we suggest a diagnostic algorithm to deal with e.g. insulin antibody formation of the IgG and/or IgE type and/or severe skin reactions resulting in poor metabolic control and often "brittle diabetes" in affected patients. This diagnostic algorithm includes step 1: Intradermal skin testing with positive and negative controls, additives and different insulin preparations; step 2: Quantification of insulin specific IgG and IgE in the serum, and step 3: Analysis of the time dependent binding/dissociation curves of the insulin neutralizing antibodies in an ex vivo/in vitro assay to assess the clinical significance of these antibodies. Based on 158 insulin treated control subjects and four patients with typical symptoms and signs representing the spectrum of immune-mediated complications subsequent to subcutaneous insulin therapy we demonstrate that the proposed stepwise approach leads to a definite diagnosis as a prerequisite for individual and successful therapy.

Approach to the patient with chest pain and nonobstructive coronary artery disease

Patients with chest pain and nonobstructive coronary artery disease (NOCAD) utilize a significant part of our health care resources. Their diagnosis and treatment can often be difficult and time consuming. A simple classification system and stepwise diagnostic approach may help to reduce unnecessary testing. Also, utilization of a chest pain clinic may be beneficial for these patients.

Approach to the patient with chest pain and nonobstructive coronary artery disease

Patients with chest pain and nonobstructive coronary artery disease (NOCAD) utilize a significant part of our health care resources. Their diagnosis and treatment can often be difficult and time consuming. A simple classification system and stepwise diagnostic approach may help to reduce unnecessary testing. Also, utilization of a chest pain clinic may be beneficial for these patients.

Acute chest pain—a stepwise approach, the challenge of the correct clinical diagnosis

Study objective: To assess the safety and the accuracy of a 4 h stepwise diagnostic approach relying on clinical judgement in unselected patients with acute chest pain. Design: Prospective cohort study. Setting: Emergency department (ED) of a tertiary care university hospital. Patients: 1288 unselected patients presenting with acute chest pain. Interventions: After history and physical examination, clinical judgement (step I), governed the need for further patient evaluation: baseline 12 lead electrocardiogramm (ECG) and laboratory examinations (step II), serial 12 lead ECG and laboratory examinations after 4 h (step III), and 4 h troponin T measurement (step IV) to exclude or to confirm a coronary origin of chest pain. Patients were followed clinically for 6 months for future occurrence of cardiac events (myocardial infarction, percutaneous transluminal coronary angioplasty (PTCA), CABG, cardiac death), any death and for accuracy of the ED diagnosis in non-coronary chest pain patients. Measurements and results: Chest pain was diagnosed to be coronary in origin in 381 and non-coronary in 907 patients, respectively. Cardiac events occurred during follow up in 240 (19%) of 1288 patients, in 233 of 381 (61%) with presumed coronary and seven of 907 (1%) with presumed non-coronary chest pain. Sensitivity, specificity, positive predictive value and negative predictive value for correct detection of coronary chest pain were 97, 86, 61 and 99%, respectively. In non-coronary chest pain patients the agreement between the ED diagnosis and the final diagnosis was good ( κ=0.71, 95% confidence interval (CI) 0.67–0.75). Conclusions: The 4 h stepwise approach guided by clinical judgement was safe for ruling out impending cardiac events in unselected patients with acute chest pain. However, more extensive evaluation is necessary for accurate rule-in of coronary chest pain.

Endoscopy in acquired immunodeficiency syndrome patients with diarrhea and negative stool studies

Background: Diarrhea is a frequent gastrointestinal symptom in patients with acquired immuno-deficiency syndrome (AIDS) and is a major source of morbidity and mortality. A stepwise diagnostic approach is often recommended to search for treatable causes. However, whether the stepwise diagnostic approach is adequate for planning treatment and whether specific treatment for infectious etiologies will affect the survival of patients with AIDS remain unknown. Methods: From March 1996 to September 1997, endoscopy was performed in AIDS patients with diarrhea, the etiology of which was not identified by noninvasive methods. Specific treatment was given according to the identified etiologies and symptomatic treatment was given for those without definite diagnosis. The clinical symptoms, signs, and duration of follow-up were recorded and survival patterns were analyzed. Results: Etiologic diagnoses were made in 26 of 40 patients (65%) who underwent endoscopic studies. Amebic colitis and cytomegalovirus colitis were the 2 leading causes of prolonged diarrhea in patients with AIDS. Thirty-five patients (87.5%) recovered after treatment. The difference in survival time after diarrhea between patients whose symptoms resolved after treatment and those who continued to have diarrhea was statistically significant ( p < 0.001). Conclusions: Endoscopic studies were helpful for the diagnosis of prolonged diarrhea in AIDS patients who had negative stool studies and did not respond to 2 weeks of empiric treatment. Specific treatment according to the results of endoscopy may improve survival in these patients. (Gastrointest Endosc 2000;51:427-32.)

Adrenal Insufficiency as a Manifestation of Disseminated Non-Hodgkin's Lymphoma

To analyze the clinical characteristics, laboratory features, and outcome in five patients who had biochemically proven adrenal insufficiency attributable to pathologically confirmed non-Hodgkin's lymphoma (NHL). We retrospectively reviewed the medical records of all patients at Mayo Clinic Rochester during the period from 1976 to 1994 to identify those with both NHL, as listed in the surgical pathology tissue registry, and adrenal insufficiency. Histologically, the patients were classified on the basis of the working formulation and the revised European-American lymphoma classification. Three patients had diffuse large cell NHL, one patient had small noncleaved NHL, and one patient had cutaneous T-cell NHL. All five patients had stage IV disease. Adrenal insufficiency was confirmed by morning and evening determinations of serum cortisol levels and cosyntropin stimulation tests. All patients demonstrated loss of circadian rhythm. The median age of the patients was 77 years (range, 60 to 89). Three of the five patients died without treatment from 5 to 22 days after assessment. One patient died of a cerebrovascular accident. Despite initiation of chemotherapy, two patients died of progressive NHL at 7 weeks and 7 months. In our experience, biochemically proven adrenal insufficiency in patients with NHL is a manifestation of clinically advanced disease in elderly patients. A stepwise diagnostic approach is critical for the appropriate management of such patients.

Syncope: Current Diagnostic Evaluation and Management

To provide a comprehensive review of the causes, current diagnostic evaluation, and treatment of syncope. New data and knowledge in this evolving field were critically analyzed by doing a MEDLINE search on syncope supplemented by selective review of English language literature citations in the Index Medicus before 1980. We reviewed approximately 200 published articles on syncope and closely related topics as well as using our own clinical experience. We selected articles if they addressed the pathophysiology of syncope, classification and causes, differential diagnosis, noninvasive and invasive evaluation, and current therapy. Syncope is a common clinical problem, occurring in 30% to 50% of the adult population. The prognosis for syncope depends on its cause. Cardiac syncope has the worst prognosis and therefore mandates thorough evaluation and prompt treatment. Diagnostic evaluation is made difficult by the transient nature of the episodes and the many causes. Noninvasive testing reveals the cause of syncope in approximately 50% of cases. More extensive evaluation, including invasive electrophysiologic studies, has assumed a larger role in defining the cause of syncope in selected patients with structural heart disease in whom a noninvasive evaluation has been nondiagnostic. Recently tilt-table studies have been proposed as a clinically useful noninvasive test for vagally mediated syncope. A rational stepwise diagnostic and therapeutic approach to patients with syncope can be developed by initially doing a careful history and physical examination followed by a noninvasive evaluation and selective use of additional, more specialized or invasive tests. Future research should focus on defining the validity and utility of current diagnostic testing in syncope and on exploring further the pathophysiology of patients with recurrent, unexplained syncope.