Thursday, June 30, 2016

Proton pump inhibitors and eosinophilic esophagitis

The question is addressed in this paper. Although EO is in general unresponsive to PPIs there is a subset that is:

Gastro-oesophageal reflux disease (GORD) is the most common oesophageal disorder, whereas eosinophilic oesophagitis (EoE) is an emerging disease unresponsive to PPI therapy. Updated guidelines in 2011 described proton pump inhibitor-responsive esophageal eosinophilia (PPI-REE), a novel phenotype in EoE patients who were responsive to PPIs.

Wednesday, June 29, 2016

Treatment of eosinophilic esophagitis

From a recent review:

If left untreated, eosinophilic inflammation induces fibrosis, angiogenesis and stricture formation, resulting finally in a so called remodelling with structural and functional damage of the organ. In addition, patients with untreated EoE are permanently at risk of experiencing food impactions...Avoidance of food allergens by elimination diets as well as anti-inflammatory drugs have both the ability to achieve these goals. Among the pharmacological options, only corticosteroids have documented efficacy, whereas alternatives have shown rather disappointing results or are still under evaluation. Of note, swallowed topical corticosteroids are at least as efficient as systemically administered corticosteroids but have fewer side effects. As such topical corticosteroids are widely used as first-line drug in the treatment of EoE, even though this compound is currently not approved for this indication by regulatory authorities.

Unfortunately, complete resolution of symptoms can be achieved with swallowed topical corticosteroids only in approximately 70% of patients despite appropriate dosing and despite correct administration of these compounds. Control of inflammation is even harder to achieve, as only in approximately 50% of patients tissue eosinophilia disappears completely under this anti-inflammatory medication. For this group of “difficult to treat” patients, therapeutic alternatives are urgently needed.

Tuesday, June 28, 2016

Painful LBBB syndrome

A paper here describes this rarely encountered entity.

Monday, June 27, 2016

Lifestyle intervention, weight loss and atrial fibrillation incidence in type 2 diabetes

From the Look AHEAD trial:

A total of 5,067 overweight or obese individuals 45 to 76 years old with type 2 diabetes without prevalent AF were randomized to either an intensive lifestyle intervention (ILI) designed to achieve and maintain weight loss through caloric reduction and increased physical activity or a diabetes support and education usual care group. Atrial fibrillation was ascertained from electrocardiograms at study examinations and hospitalization discharge summaries. Multivariable Cox models were used to estimate the intention-to-treat effect of the intervention adjusting for baseline covariates. During a mean follow-up of 9.0 years, 294 incident AF cases were identified. Rates of AF were comparable in the ILI and diabetes support and education groups (6.1 and 6.7 cases per 1,000 person-years, respectively, P = .42). The intervention did not affect AF incidence (multivariable hazard ratio [HR] 0.99, 95% CI 0.77-1.28). Similarly, neither weight loss nor improvement in physical fitness during the first year of the intervention was significantly associated with AF incidence: multivariable hazard ratio (95% CI) comparing top versus bottom quartile was 0.70 (0.41-1.18) for weight loss and 0.88 (0.55-1.43) for physical fitness improvement.

In a large randomized trial of overweight and obese individuals with type 2 diabetes, an ILI that induced modest weight loss did not reduce the risk of developing AF.

This is a little disappointing. There is evidence that obesity is a risk factor for atrial fibrillation and it is appealing to believe that lifestyle modification is an effective treatment. In light of this study the best we can say at this point is that the evidence is mixed.

Fluid overload after fluid resuscitation

It happens and may be unavoidable. Strategies to deal with it in the post resuscitation period are needed. Review here.

Sunday, June 26, 2016

Environmental etiologic factors for eosinophilic esophagitis

Like many chronic conditions EO represents an interaction between genetics and environment. From a recent review:

Few studies have been conducted, however a consistent inverse association between EoE and H. pylori has been described. Several studies suggest a weak association between season and EoE diagnosis, but the evidence is inconclusive. EoE has also been associated with early life factors, including Cesarean delivery and antibiotic use. Larger studies are needed to evaluate these associations more thoroughly. Several papers have speculated the potential for anti-secretory agents to contribute to EoE.

Saturday, June 25, 2016

Mineralocorticoid excess and related syndromes

This was the topic of a recent review in Advances in Chronic Kidney Disease. Below are some take home points.

Hyperaldosteronism has deleterious effects beyond hypertension and hypokalemia such as hypertension independent LVH, myocardial fibrosis and an increase in other organ manifestations (eg hemorrhagic stroke) compared to the general population of hypertensive patients.

Sporadic primary aldosteronism

About a third are due to an adrenal adenoma for which unilateral adrenalectomy is the treatment of choice. About two thirds have bilateral adrenal hyperplasia in which the biochemical disturbances tend to be milder and for which medical management with aldosterone receptor antagonists is the treatment of choice.

Familial hyperaldosteronism type I

AKA glucocorticoid responsive hyperaldosteronism.

Reported in 1966.

Autosomal dominant.

Rare among causes of hyperaldosteronism but the most common form of monogenic hypertension.

As a result of the mutation aldosterone secretion is under the control of ACTH, thus treatment is with a glucocorticoid, preferably dexamethasone due to its long duration of action and minimal mineralocorticoid effect. Treatment may also include standard antihypertensive therapy including mineralocorticoid antagonists.

Familial hyperaldosteronism type II

Described in 1992.

Autosomal dominant.

Not suppressible by glucocorticoid.

Like sporadic hyperaldosteronism, it can be associated with adenoma or hyperplasia and the treatment is the same as in the sporadic form.

Familial hyperaldosteronism type III

Described 2008.

Not suppressible by glucocorticoid.

Massive hyperplasia.

Severe presentation with treatment resistance.

Liddle syndrome

Described 1963.

Though rare, second most common cause of monogenic hypertension.

Numerous mutations discovered, all of which cause increased activity of the epithelial sodium channel (ENaC).

Aldosterone levels low.

Treatment is with ENaC antagonists (triamterene, amiloride) but not mineralocorticoid antagonists such as spironolactone.

Apparent mineralocorticoid excess

Described 1977.

Autosomal recessive.

Third most common form of monogenic hypertension.

Local (renal tubular) deficiency of 11 beta hydroxysteroid dehydrogenase type 2 resulting in defective local conversion of cortisol to cortisone. The result is a local excess of cortisol, which has mineralocorticoid activity.

Treatment is with potassium sparing diuretics and possibly dexamethasone.

Licorice ingestion mimics this syndrome by causing inhibition of the intracellular enzyme.

Congenital adrenal hyperplasia

This is a group of diseases associated with numerous enzyme deficiencies. Only 17 alpha hydroxylase and 11 beta hydroxylase deficiencies cause mineralocorticoid excess syndromes. These result from an accumulation of precursors in the steroid biosynthetic pathway which possess mineralocorticoid activity. Glucocorticoid administration is the treatment.

Friday, June 24, 2016

Premature ventricular contractions: everything you wanted to know and more

A detailed review was recently published, which should be read in the original. Below are a few key issues covered.


Known or purported mechanisms include automaticity, triggered activity and re-entry. Automaticity causes ventricular ectopy (VE) by premature depolarization of pacemaker cells. This results from a shortening of the time it takes for phase 4 diastolic depolarization to reach threshold, due to an increased slope of diastolic depolarization or other mechanisms.

So called triggered activity is the result of afterdepolarizations, which could take the form of delayed (DAD) or early afterdepolarizations (EAD). DAD occur in phase 4 and are believed to be related to increased intracellular calcium concentrations due to a variety of mechanisms (eg catecholamine effects) with increased cAMP levels as a final common pathway. This in turn leads to a transient inward depolarizing sodium current generated by the Na/Ca exchanger. DAD is believed to be the mechanism of adenosine sensitive RVOT ectopy.

The mechanisms of EAD are less clear. Because EAD occur in phase 3 they increase repolarization time and appear to be instrumental in causing arrhythmias in the setting of a long QT interval.

Re-entry, once thought to be the primary mechanism of VE, is now in doubt as an important cause of PVCs.

The PVC coupling interval may provide a clue as to the mechanism but this is not entirely clear. A fixed coupling interval implies re-entry (if such exists in man) or triggered activity. Variable coupling intervals imply automaticity. Variable coupling intervals with equal or mathematically related inter-ectopic intervals are designated as parasystole which is usually associated with structural heart disease.

Are PVCs associated with harm?

It is useful to approach this question with respect to the presence or absence of structural heart disease. In both acute ischemia and chronic structural heart disease we know that they are associated with negative outcomes though it is less clear whether as a marker or a cause.

What about patients with no structural heart disease? In such patients VE was traditionally thought to be almost universally benign, based primarily on this paper from 1985 by Harold Kennedy and others. Drawing from a larger database that has accumulated since that time, this notion has been challenged, and there may be risk in some patients. This risk is poorly characterized with the exception of two categories: certain purely electrical heart diseases (channelopathies) and the potential for chronic frequent PVCs to cause a dilated cardiomyopathy (DCM). In purely electrical diseases a single PVC may trigger a life threatening event. From the article:

PVCs can trigger VF or polymorphic VT in patients with or without structural heart disease. 6 30 Some features of PVCs can help to identify “malignant PVCs” that have the potential of triggering VF in some patients. Most often PVCs are not tightly coupled to prior sinus beats; however, in certain conditions, tightly coupled PVCs have been described to trigger VF. This has been described for patients with Brugada syndrome, 31 early repolarization syndromes, 32 idiopathic VF, 33 or in the setting of acute myocardial infarction. 7 In the absence of these conditions, malignant ventricular arrhythmias are rare but have been reported and often have been triggered by tightly coupled PVCs. 6 34 No absolute cutoff value for a tight coupling interval has been defined, although most often the PVC coupling interval was less than 400 ms in these circumstances. 6 Other parameters that need to be assessed include the QT interval and the presence of nonsustained VT, including rate and morphology. More malignant arrhythmias have shorter cycle lengths, 35 and in 1 report, the coupling interval of the second beat of the nonsustained VT was found to be shorter in patients with VF compared with patients without VF. 36

It must be kept in mind that in some conditions (eg LQTS, hereditary and acquired) not all triggering PVCs are short coupled.

Concerning PVC induced DCM recent findings challenge the notion that this is caused chiefly by RVOT ectopy. Though RVOT ectopy is a known cause, DCM can result from VE originating from other foci. Also recently challenged is the idea that 15% of heartbeats is necessarily the ectopic frequency threshold for the development of DCM. The critical frequency is actually quite variable and is likely influenced by other risk factors, one of which is PVC QRS width, which is roughly directly proportional to the risk of DCM. A cutoff of 150 ms has been suggested. Epicardial origin of PVCs is associated with a wider QRS and greater DCM risk. Finally, interpolation of PVCs is also associated with a greater DCM risk. PVC induced DCM was once thought to be a variant of tachycardia mediated DCM but is now believed due to different mechanisms. It should be noted that in patients who already have structural disease for other reasons, frequent PVCs can lead to further deterioration of ventricular function.


Beta blockers are first line despite low efficacy due to their favorable safety profile. I-C antiarrhythmic drugs have stronger efficacy and are considered the next line of treatment provided the patient has no structural heart disease. The concern that these drugs increase the risk of SCD when used to treat PVCs is restricted to patients with structural heart disease. Careful assessment and appropriate expertise are required. Amiodarone is an option for patients who do have structural heart disease. Once DCM ensues due to frequent PVCs therapeutic options become limited for the above stated reasons. Suppression of VE with amiodarone has been reported to reverse DCM in that situation.

Catheter ablation is a preferred option in selected patients and is discussed in detail in the article.

Thursday, June 23, 2016

Vagal atrial fibrillation

This entity has long been known. It represents one group of mechanisms accounting for the increased risk of atrial fib with athletic conditioning. Review here.

Wednesday, June 22, 2016

How should we define valvular and non-valvular atrial fibrillation?

When the NOACs were first introduced atrial fibrillation associated with any hemodynamically significant valvular disease was considered valvular AF, excluding patients for treatment with a NOAC. Subsequently NOAC indications with respect to type of valve have been liberalized somewhat. The present consensus seems to be that patients considered to have valvular AF are those with rheumatic mitral disease, a valvular prosthesis (either tissue or mechanical) and possibly those with MV repair. Here is a recent review.

Tuesday, June 21, 2016

Walking speed, walking distance and mortality

From a recent review:

Although treadmill exercise testing can provide an assessment of cardiorespiratory fitness, which serves as an independent prognostic indicator, numerous studies now suggest that usual gait speed, time, or distance covered during walk performance tests and weekly walking distance/time are powerful predictors of mortality and future cardiovascular events in selected patients. This review summarizes the relation between these variables and their association with cardiovascular and all-cause mortality, with specific reference to potential underlying mechanisms and implications for the clinician. Contemporary health care providers have escalating opportunities to promote lifestyle physical activity using pedometers, accelerometers, and smartphone-based health and wellness applications. In conclusion, fitness and/or ambulatory indexes should be considered a “vital sign” in middle-aged and older adults.

Monday, June 20, 2016

Giving vasoactive drugs through a peripheral IV

Controversy exists as to whether vasopressors can be given through a peripheral IV and practices vary from institution to institution. Here is a systematic review. Although the review was beset with significant methodologic issues some conclusions were drawn. From the review:

The available data do allow the conclusion that administration of vasopressors through the peripheral intravenous line appears to be associated with more local tissue and extravasation events compared with that through central venous catheters, although the events occur with both types of venous access. Additionally, when peripheral intravenous lines are used, local tissue and extravasation events seem to increase when vasopressors are administered through distal sites for an extended period. Therefore, peripheral catheters should be viewed as a bridge to central access, given the apparent higher rate of adverse events with prolonged peripheral administration of vasopressors.

Sunday, June 19, 2016

Weight reduction, pericardial adipose tissue and cardiac structure in patients with atrial fibrillation

From a recent study:


We prospectively performed cardiac magnetic resonance imaging on 87 participants with AF undergoing either structured weight management (intervention) or general lifestyle advice (control). We measured pericardial adipose tissue, atrial and ventricular volumes, and myocardial mass at baseline and 12 months.


In total, 69 participants underwent baseline and 12-month follow-up cardiac magnetic resonance imaging (intervention n = 36 and controls n = 33). From baseline to 12 months, weight loss (kg, mean [95% CI]) was greater in the intervention group from 101.5 kg (97.2-105.8 kg) to 86.5 kg (81.2-91.9 kg) as compared with controls from 102.6 kg (97.2-108.1 kg) to 98.7 kg (91.0-106.3 kg) (time-group interaction P less than .001). The intervention group showed a reduction in left atrial volumes (mL) from 105.0 mL (98.9-111.1 mL) to 96.4 mL (91.6-101.1 mL), whereas the change in the control group was from 108.8 mL (99.6-117.9 mL) to 108.9 mL (99.8-118.0 mL) (time-group interaction P less than .001). There was a decline in pericardial adipose tissue (cm3) from 140.9 cm3 (129.3-152.4 cm3) to 118.8 cm3 (108.1-129.6 cm3) and myocardial mass (g) from 137.6 g (128.1-147.2 g) to 123.1 g (114.5-131.7 g) in the intervention group, whereas the change in the control group was from 143.2 cm3 (124.6-161.7 cm3) to 147.2 cm3 (128.9-165.4 cm3) for pericardial adipose tissue and 138.3 g (124.8-151.8 g) to 140.7 g (127.4-154.1 g) for myocardial mass (both variables, time-group interaction P less than .001).


Weight reduction results in favorable structural remodeling and a reduction in pericardial adipose tissue burden.

Saturday, June 18, 2016

Measles and pertussis risk related to vaccine refusal

From a JAMA report:

Conclusions and Relevance A substantial proportion of the US measles cases in the era after elimination were intentionally unvaccinated. The phenomenon of vaccine refusal was associated with an increased risk for measles among people who refuse vaccines and among fully vaccinated individuals. Although pertussis resurgence has been attributed to waning immunity and other factors, vaccine refusal was still associated with an increased risk for pertussis in some populations.

Friday, June 17, 2016

Legionnaires' disease review

From the summary and introduction:

Since first identified in early 1977, bacteria of the genus Legionella are recognised as a common cause of community-acquired pneumonia and a rare cause of hospital-acquired pneumonia. Legionella bacteria multisystem manifestations mainly affect susceptible patients as a result of age, underlying debilitating conditions, or immunosuppression. Water is the major natural reservoir for Legionella , and the pathogen is found in many different natural and artificial aquatic environments such as cooling towers or water systems in buildings, including hospitals. The term given to the severe pneumonia and systemic infection caused by Legionella bacteria is Legionnaires' disease...

Bacteria of the genus Legionella were discovered during the investigation of a major pneumonia outbreak in members of the American Legion attending their annual meeting in 1976 in Philadelphia. 1 The causative microorganism was an unknown bacterium and was designated Legionella pneumophila . The term given to the infection was Legionnaires' disease, which refers to the pneumonic form of legionellosis. 29 (16%) of 182 patients died, and this new type of pneumonia did not respond to β-lactam antibiotics...

Macrolides, doxycycline, and quinolones are the main effective antibiotics...

According to the review LD is under diagnosed and under reported. In contrast to pneumococcal pneumonia the pathogenesis is inhalation rather than aspiration. The urine antigen is the first line test though there are limitations as described in the text.

Thursday, June 16, 2016

The internist as both specialist and generalist

Here's a quote from William Osler that explains why:

There are, in truth, no specialties in medicine, since to know fully many of the most important diseases a man must be familiar with their manifestations in many organs.

Wednesday, June 15, 2016

HIT and the spectrum of thrombocytopenia in the ICU

Here’s a great review from last December. Some key points:

HIT is a state of extreme hypercoagulability. Over 50% of patients who have it develop thrombosis.

Thrombosis can involve both the arterial and venous sides.

Though usually macrothrombosis, some patients will have microthrombosis with a picture resembling DIC.

Pathyphysiology: The platelet factor 4-heparin complex stimulates an antibody response consisting of platelet activating IgG. Platelet derived microparticles have procoagulant activity and monocytes become activated to express tissue factor.

HIT tends to be overdiagnosed and represents less than 1% of ICU thrombocytopenia. Most patients with HIT antibodies don’t actually develop HIT, contributing to the problem of overdiagnosis.

An important mimic of HIT: Non-HIT related DIC which depletes natural anticoagulants (ptn C and AT) especially in the setting of shock and shock liver can cause symmetrical peripheral limb gangrene thus mimicking some forms of HIT.

LE DVT with or without PE is the most common thrombotic complication.

Adrenal vein thrombosis occurs in 2% of cases, which can lead to adrenal hemorrhagic necrosis and adrenal crisis.

Arterial thrombosis sites in order of decreasing frequency: LE, cerebral, coronary, mesenteric, UE.

Two potential mechanisms for ischemic limb necrosis: venous gangrene in the face of warfarin induced protein C depletion OR arterial thrombosis.

Concerning diagnosis, from the review:

HIT is a ‘clinical–pathological’ syndrome [30,31][30,31], that is, the patient should exhibit both a clinical picture consistent with HIT, for example, thrombocytopenia and/or thrombosis bearing a temporal relationship with a preceding immunizing exposure to heparin (‘clinical’), and the serological profile of HIT, namely detectability within patient serum (or plasma) of the pathognomonic, heparin-dependent, platelet-activating antibodies (‘pathological’). A recent consensus conference statement recommended the following diagnostic framework [32]: intermediate or high-probability clinical picture (scoring at least 4 points in the 8-point 4Ts scoring system [25–28][25–28][25–28][25–28]) and heparin-dependent, platelet-activating antibodies, as shown either by a positive serotonin-release assay (SRA) [33,34][33,34] or heparin-induced platelet activation test [35] along with a corroborating positive PF4-dependent immunoassay, such as an enzyme-immunoassay (EIA) [36]. The approach reduces risk of HIT overdiagnosis [37[black small square]].

New concepts of treatment. From the review:

Only argatroban, a direct thrombin inhibitor, is currently approved to treat HIT in the USA (lepirudin has been discontinued). However, no controlled studies are available to show that argatroban is effective to treat HIT. The approval trials [85,86][85,86] did not require positive laboratory testing for HIT, and so most enrolled patients likely did not have HIT, in contrast to the (historical) controls who were antibody-positive. Further, the high limb amputation rate in the argatroban-treated study patients (13.7%) [21] raises concerns about argatroban-warfarin overlap, a situation with risk for venous limb gangrene [87,88][87,88] (both agents prolong the INR [89]). Argatroban is also a costly medication.

Indirect factor Xa inhibitors
Indirect (antithrombin-dependent) factor Xa inhibitors, such as danaparoid (not available in the USA) and fondaparinux, have advantages over argatroban, and I prefer using one of these to treat HIT [5,36][5,36]. Neither pose risk of APTT confounding, as drug levels are measured directly (as antifactor Xa levels). However, reduced dosing (after a full loading dose) is appropriate in renally-compromised patients [56[black small square][black small square]]. Prophylactic dosing is probably appropriate for ICU patients, unless there is thrombosis or strong suspicion (or confirmation) of HIT. Fondaparinux is increasingly being used to treat HIT despite its off-label status for this indication.

Tuesday, June 14, 2016

Left atrial appendage occlusion for stroke prevention in atrial fibrillation

From a recent review:

A single device has now received regulatory approval for patients at increased risk of stroke but in whom there are felt to be increased risks of bleeding making chronic anticoagulation less optimal. The approved indication for the WATCHMAN device in the US is for patients with nonvalvular AF who are at increased risk for stroke and systemic embolism based on CHADS 2 or CHA 2 DS 2 -VASc scores, deemed by their physicians to be suitable for warfarin, but who “have an appropriate rationale to seek a nonpharmacologic alternative to warfarin. “In Europe, LAA occlusion devices have received CE mark and are currently being used in clinical practice. Currently the European Society of Cardiology guidelines on AF 117 recommend that LAA closure may be considered in patients with high stroke risk who also have contraindications for long-term oral anticoagulation.

Monday, June 13, 2016

Clinical features of hairy call leukemia

Think of it when you see pancytopenia (or bicytopenia) and splenomegaly without peripheral lymphadenopathy. From a recent review:

The diagnosis of HCL is not usually difficult, given its characteristic clinical, morphologic, and immunophenotypic features. Most patients have splenomegaly in the absence of peripheral lymphadenopathy, and a variable degree of cytopenias, including monocytopenia. Typical hairy cells are evident in the peripheral blood on a routine smear (or on a buffy coat preparation) in more than 90% of cases.

Sunday, June 12, 2016

Eosinophilic esophagitis as an atopic disease

From a recent review:

Eosinophilic Esophagitis (EoE) is a classic atopic disease as it shares features with other atopic disease on all levels including pathogenesis, genetics, epidemiology, and treatment options. EoE has elements of Th2 pathogenesis with increase levels of Th2 cytokines (IL4, 5, and 13). In addition, it shares atopic genetic risk factors including thymic stromal lymphopoietin (TSLP) loci as a risk factor in genome wide association studies. EoE patients have a higher rate of other atopic disease (asthma, allergic rhinitis and food allergy) compared to the general population indicating their atopic phenotype. Like asthma, atopic dermatitis or food allergy, EoE has increased in the last 20 years. Treatment options include the basic principle of other atopic diseases include using topical steroids or avoidance of the triggers (food or pollen).

Sunday, June 05, 2016

Practical aspects of the FUO work up

This article in the American Journal of Medicine argues for a focused clinical approach rather than a shotgun approach to the diagnosis of fever of undetermined origin. Due to the complexities of the condition there are difficulties with such an approach. There is certainly no algorithm to apply. Nevertheless certain clinical clues can help guide the diagnostic approach.

Despite the use of outmoded terminology (eg hypernephroma for renal cell carcinoma and periarteritis nodosa for polyarteritis nodosa) and questionable assumptions (eg that fever curve patterns reliably point to the correct diagnosis) the review, which is available as free full text, makes some helpful points:

First, confirm that your patient's illness meets the criteria for FUO

The coding calculators in your EMR may try and force you into this designation prematurely. Do not succumb!

Attempt to classify the patient's FUO according to the two bases for classification

These are classical (infectious, neoplastic, rheumatic/inflammatory) and host based (immunocompetent, HIV, immunosuppressive therapy, travel history).

Look for historical features that suggest or eliminate certain categories

Rigors, for example, eliminate the rheumatologic category.

Look for organ involvement clues

SLE, for example, tends to spare the liver.

Laboratory clues may help

From the paper:

Diagnostic specificity of nonspecific laboratory abnormalities is increased when considered together. Degree of test abnormality itself limits diagnostic possibilities, for example, an elevated erythrocyte sedimentation rate is very sensitive/not specific, but a highly elevated erythrocyte sedimentation rate (greater than100 mm/h) narrows diagnostic possibilities to very few entities. Similarly, 6% atypical lymphocytes (drug fever, toxoplasmosis) have a different differential than 36% atypical lymphocytes (Epstein-Barr virus, cytomegalovirus). Nonspecific findings may be exclusionary clues, for example, eosinophilia argues strongly against typhoid/enteric fever...

In a fever of unknown origin, an isolated alkaline phosphatase elevation suggests lymphoma.21, 23, 26 Serum protein electrophoresis also may provide diagnostic clues, for example, elevated α1/α2 globulin elevations (lymphoma, systemic lupus erythematosus); monoclonal gammopathy (multiple myeloma, hyper-IgD syndrome, multicentric Castleman's disease); and polyclonal gammopathy (human immunodeficiency virus, cytomegalovirus, cirrhosis, sarcoidosis, malaria).

Saturday, June 04, 2016

Overview of eosinophilic esophagitis

Key points from a recent paper:


This chronic inflammatory disease of the esophagus, once thought to be rare when first described 20 years ago, is now known to be the second most common chronic esophageal disorder known, next to GERD, with a prevalence similar to that of inflammatory bowel disease.

Etiology and pathophysiology

Largely unknown but food allergens are believed to play a role. Histology is characterized by eosinophilic infiltration.

Clinical presentations and complications

Dysphagia and food impaction.

Friday, June 03, 2016

Cryptogenic stroke

This recent Clinical Practice piece in NEJM is a difficult and cumbersome read. Here is my effort to distill it down to some key points.

The definition of cryptogenic stroke (CS) is unclear.

CS is generally defined as stroke which remains unexplained as to cause after adequate evaluation. However that concept is vague due to uncertainty about what constitutes an adequate evaluation. Moreover, some consider uncertain presentations with more than one plausible substrate identified as CS. The latter category is not considered CS for purposes of discussion in the paper. In an attempt at clarity the authors subdivide CS into 1) unknown cause after “standard evaluation” (CSSE) and 2) unknown cause after “advanced evaluation” (CSAE).

Standard evaluation is defined as: echo (TTE and/or TEE depending on clinical circumstances), in hospital telemetry or 24 hour Holter, stroke imaging (it doesn't specify whether this is CT and/or MRI), and noninvasive vascular imaging of the head and neck (CTA or MRA). Advanced evaluation consists of: invasive angio, transcranial doppler, vasculitis tests, outpatient monitoring up to 4 weeks and thrombophilia tests (arterial thrombophilia tests in unselected patients but venous thrombophilia tests only in those with suspected intracardiac shunt). A third category called “specialized evaluation” exists. It consists of: genetic tests, LP, brain biopsy, advanced cardiac testing and 1 to 3 year monitoring via an implanted monitor.

Causes of CS

A long list of rare causes is contained in the on line supplement to the paper. Here are the more important ones:

Occult atherosclerosis (nonstenosing but unstable plaques, intracranial and extracranial)

Thoracic origin stenosis

Nonatherosclerotic arteriopathies (eg dissection, vasculitis)

Hypercoagulable states (arterial in unselected cases, venous if paradoxical embolism is considered)

Low burden atrial fibrillation

Dilated cardiomyopathy

Paradoxical embolism

Likely causes by age

Realizing considerable overlap they can be categorized as follows:

18-30: Dissection is most common. Also consider thrombophilia and structural (congenital) heart disease.

31-60: Premature atherosclerosis, structural heart disease

Over 60: occult atrial fibrillation

Published stroke classification schemes may guide evaluation.

The CCS (Causative classification of strokes) (this is a useful web based tool) and ASCOD (atherosclerosis, small vessle disease, cardiac pathology, other causes, dissection) are emerging as more useful classifications than the traditional TOAST categories because they assign fewer cases as CS.

Recommendations for evaluation of CS

Recommended tests for the various levels of evaluation were listed in the first section above. Certain points warrant elaboration:

No particular order of testing was given within categories.

Small deep white matter infarcts, which might otherwise be categorized as CS, may not need advanced testing in patients over 50 or who have standard vascular risk factors.

Recommended vasculitis serologic tests consist of ESR, CRP, ANA, RF and ANCA.

Transcranial doppler monitoring for up to 60 minutes may detect covert microemboli, either of cardiac or arterial origin.

Invasive, as compared to noninvasive, angiography better evaluates medium and small arteries and may be useful in detecting vasculitis (which may be associated with negative serologic tests) and other unusual arterial diseases.

Special considerations in atrial fibrillation

These are detailed in the appendix available on line. Some of the recommendations differ from the secondary prevention guidelines.

The author recommends that when AF is detected during hospitalization anticoagulation with a NOAC be started by the time of discharge. This is a more aggressive approach than found in the guidelines and would raise some bleeding concerns in my mind. The guidelines, in contrast to the review article, state no preference between warfarin and NOACs other than to say that rivaroxaban has a IIa recommendation while warfarin, dabigatran and apixaban have a class I recommendation. Moreover, the guideline recommended start time is “within 14 days” in many strokes but delayed beyond that time in large infarcts or those with increased bleeding risk. Given the short hospital stay for most strokes these days the review author seems to favor anticoagulation significantly earlier than what the guidelines call for. Moreover, given the rapid onset of action of NOACs this approach would have the patient fully anticoagulated just a few days after stroke onset.

For CSSE the paper recommends discharge with ambulatory monitoring for 30 days, and on a NOAC if there are multiple AF risk factors but on antiplatelets if not.

For patients with negative 30 day monitoring and no AF risk factors the author would dismiss AF from further consideration and treat with antiplatelet therapy. If AF risk factors are present the author would recommend an implanted monitor with consideration for continuing the NOAC for a year followed by reassessment.

If low burden AF is found on 30 day monitoring the recommendation is to continue the NOAC but if no AF risk factors are present to consider stopping it after a year.

Further reading: here is a CS resource on the American Stroke Association website.