Grady Morning Report: What are the most recent diagnostic criteria for MS?

The Bottom Line: Despite the incorporation of MRI and other paraclinical evidence into the diagnostic scheme, careful clinical evaluation and judgment, and the principle of “no better explanation” remain the most important aspects of MS diagnosis and should not be replaced by any diagnostic test.

Reference: Milo R, Miller A. Revised diagnostic criteria of multiple sclerosis. Autoimmun Rev. 2014 Apr-May;13(4-5):518-24. 

Summary: Over the years, several sets of criteria have been proposed for the diagnosis of MS, based on the principles of dissemination in space (DIS) and dissemination in time (DIT) of CNS lesions, and the exclusion of other diseases with similar characteristics. With each revision, new diagnostic criteria modified disease definitions and diagnostic thresholds, while aiming at maintaining sensitivity and improving specificity. According to the older Schumacher and Poser criteria, MS can be diagnosed clinically by demonstrating 2 separate attacks (fulfilling DIT criteria) involving at least 2 different areas of the CNS (fulfilling DIS criteria). The 2001 McDonald criteria and their 2005 revision incorporated defined magnetic resonance imaging (MRI) criteria for DIS and DIT that provided guidance on how to diagnose MS after CIS. The most recent 2010 McDonald criteria simplify requirements for DIS and DIT and may allow for an earlier diagnosis of MS from a single baseline brain MRI if there are both silent gadolinium-enhancing and nonenhancing lesions.


Grady Morning Report: What are the current guidelines concerning the management of acute pulmonary embolism (PE)?

The Bottom Line:

Only one of the phase 3 clinical trials investigating the use of new direct oral anticoagulants in patients with VTE reported efficacy results for the subgroup of patients with acute PE and RV dysfunction. Among patients with elevated NT‐proBNP levels, recurrent VTE occurred in 15 of 454 patients in the edoxaban cohort and in 30 of 484 patients in the warfarin group.

A new trial, the Pulmonary Embolism International Trial (PEITHO‐II) will focus on the safety, efficacy and cost‐effectiveness of dabigatran in the treatment of patients with acute intermediate‐risk PE. Patients will be treated with low molecular weight heparin for at least 72 hours followed by dabigatran treatment for 6 months.

References: Klock FA et al. Management of intermediaterisk pulmonary embolism: uncertainties and challenges. Eur J Haematol. 2015 Dec;95(6):489-97. doi: 10.1111/ejh.12612. Epub 2015 Jul 15.

Link to current trial (still recruiting patients):


Reperfusion Treatment

A. The Pulmonary Embolism Thrombolysis Trial (PEITHO) compared, in a double‐blind manner, fibrinolysis with tenecteplase plus heparin vs. placebo plus heparin in 1005 patients with acute PE. Eligible patients had RV dysfunction, plus myocardial injury; that is, they were at intermediate‐high risk of an adverse early outcome. The primary outcome, a composite of all‐cause death or hemodynamic decompensation/collapse, was significantly reduced with tenecteplase. On the other hand, there was an increased incidence of hemorrhagic stroke after fibrinolytic treatment with tenecteplase; major non‐intracranial bleeding events were also increased in the tenecteplase group compared with placebo. This study strongly argues against the standard application of thrombolysis in hemodynamically stable PE patients.

B. Catheter‐directed techniques are considered an alternative to surgery. The safety and efficacy of pharmacomechanical fibrinolysis is supported by the results of a recent trial which enrolled 150 patients with submassive (intermediate‐risk) or massive (high‐risk) PE. Due to the lack of high‐quality studies in patients with PE in general as well as in patients with intermediate‐risk PE specifically, the safety and efficacy of these interventions remain unknown.

Anticoagulation Treatment

New non‐vitamin K‐dependent oral anticoagulants (NOACs), in particular direct factor IIa (thrombin) and factor Xa inhibitors, were developed and tested in large phase‐3 randomized clinical trials. A meta‐analysis of the phase III clinical trials on VTE showed that new oral anticoagulants were associated with a significantly lower risk of major as well as fatal hemorrhage compared to VKA treatment. The experience with NOACs in current trials on intermediate risk PE is limited.



Kokko Conference: Is Vitamin B12 deficiency one of the etiological causes of pancytopenia?

The Bottom Line: The etiological causes of pancytopenia vary depends on patients’ age, gender, country, and other conditions. Vitamin B12 deficiency is the most common treatable cause of pancytopenia.


Yokuş O, Gedik H. Etiological causes of pancytopenia: A report of 137 cases. Avicenna J Med. 2016 Oct-Dec;6(4):109-112.

ARTICLE mentioned in Conference:

Stabler, SP. Clinical practice. Vitamin B12 deficiencyN Engl J Med. 2013 Jan 10;368(2):149-60. doi: 10.1056/NEJMcp1113996.

Kokko Conference: Does TTP (thrombotic thrombocytopenic purpura) result in ARDS (acute respiratory distress syndrome)?

The Bottom Line: Life-threatening ARDS can be associated with TTP. Early recognition of ARDS associated with TTP and timely EP is critical to a favorable outcome.

Summary: Experience suggests that ARDS may occur as a clinical feature of either de novo or secondary TTP; therefore, all patients with ARDS should be evaluated for unrecognized TTP. A high index of suspicion is crucial when a patient with ARDS presents with unexplained thrombocytopenia and MAHA, with or without neurological or mental changes. Because exchange plasmapheresis is a life-saving measure, unexplained thrombocytopenia and MAHA should be sufficient criteria to make the presumptive diagnosis of TTP for the initiation of exchange plasmapheresis.

Reference: Chang JC, Aly ES. Acute respiratory distress syndrome as a major clinical manifestation of thrombotic thrombocytopenic purpuraAm J Med Sci. 2001 Feb;321(2):124-8.

Kokko Conference: Do protease inhibitors lead to improved outcomes in AL cardiac amyloidosis?

The Bottom Line: . In a study of diflunisal in ATTR cardiac amyloidosis (both mutant and wt), stable mean left ventricular (LV) mass, LVEF and cardiac biomarkers were seen during the course of therapy.  Nephrotoxicity and volume overload was observed as AEs. A RCT of diflunisal for familial amyloid polyneuropathy (FAP; caused by mutant ATTR) reported neurological stability at 2 years in 29.7 % of patients in the diflunisal arm versus 9.4 % of the placebo arm.  Tafamidis, a kinetic stabilizer of TTR protein, is active in FAP and leads to a delay in peripheral neurologic impairment, with minimal AEs.  A phase 2 study of tafamidis in ATTR amyloid cardiomyopathy showed TTR stabilization in
97 % of wt patients with mild to moderate CHF.

References:  Chakraborty R. et al.  Newer Therapies for Amyloid Cardiomyopathy.  Curr Heart Fail Rep.  2016 Oct;13(5):237-246.

Summary: OLT remains the benchmark for treatment of ATTR amyloidosis; however, progression of cardiac amyloidosis after OLT due to an increase in the wild:mutant TTR ratio is concerning. Development of BTTR stabilizers is a promising arena in hereditary amyloidosis and further studies are needed to ascertain survival benefit in those with cardiac involvement.

Grady Report: What are the current guidelines for the pharmacological management of prostatitis?

The Bottom Line: For healthcare providers, the focus of therapy is symptomatic relief. The first therapeutic measure is often a 4- to 6-week course of a fluoroquinolone, which provides relief in 50% of men and is more efficacious if prescribed soon after symptoms begin. Second-line pharmacotherapy involves anti-inflammatory agents for pain symptoms and alpha-adrenergic receptor antagonists (alpha-blockers) for urinary symptoms. Potentially more effective is pelvic floor training/biofeedback, but randomized controlled trials are needed to confirm this. Third-line agents include 5alpha-reductase inhibitors, glycosaminoglycans, quercetin, cernilton (CN-009) and saw palmetto.  Pain and urinary symptoms can be ameliorated with anti-inflammatories and alpha-blockers.

Summary: CP/CPPS has many clinical presentations and treatment options, with fluoroquinolones as the only FDA-approved first-line agents. Combination therapy of an α-blocker for ≥12 weeks with a fluoroquinolone may be considered a multimodal first-line therapy. Differentiating CP/CPPS from the other NIH prostatitis subtypes helps healthcare professionals design treatment plans that optimize response.

Reference: Murphy AB, et al. “Chronic prostatitis: management strategies.Drugs 2009; 69(1):71-84.

When should a head CT be performed prior to a lumbar puncture?

Lumbar puncture/Procedure considerations/Neuroimaging in Dynamed

The section on Testing to Consider Prior to Performing an LP in DynaMed’s entry for lumbar puncture summarizes two prospective cohort studies and lists clinical findings such as age and aspects of clinical history and specific neurologic findings that were predictive of cranial lesions that contraindicated LP: age > 60 years, immunocompromised status, history of central nervous system disease, history of seizure within 1 week, abnormal level of consciousness, and focal findings on neurological exam.

Hasbun R, Abrahams J, Jekel J, Quagliarello VJ. Computed tomography of the head before lumbar puncture in adults with suspected meningitis. N Engl J Med. 2001 Dec 13;345(24):1727-33. 235 patients with suspected meningitis received CT before lumbar puncture. RESULTS: Abnormal CT in 24% of patients in the study; 5% had evidence of a mass effect. Factors associated with an abnormal head CT were age ≥ 60 years, immunocompromised, history of CNS disease, history of seizure within one week before presentation.

Gopal AK Cranial computed tomography before lumbar puncture: a prospective clinical evaluation. Arch Intern Med. 1999 Dec 13-27;159(22):2681-5. Of 113 patients with urgent circumstances necessitating CT, 15% of CTs showed new lesions but only 2.7% had lesions that contraindicated LP

jkn 2/16

Is there a systematic evaluative approach to adults with thrombocytopenia?

The Bottom Line: See Figure 1, p. 193, “Algorithm for workup of thrombocytopenia based on observation of the peripheral blood film.”

Reference: Stasi R.  How to approach thrombocytopenia.  Hematology Am Soc Hematol Educ Program. 2012;2012:191-7. 

Summary: The initial approach to determining the cause of thrombocytopenia is based on the patient’s history of underlying diseases and drug treatments, on physical examination, and on careful examination of the peripheral blood smear. The 2 most common causes of a low platelet count in the absence of other hematologic abnormalities and no evidence of a multisystem disease are ITP and DITP. The most common cause of a low platelet count in pregnancy is GT. In hospitalized and critically ill patients, the diagnosis of thrombocytopenia is often challenging due to the presence of several potential etiologies, including drugs and infections. Examination of the BM with aspiration and biopsy is warranted in patients with severe or worsening thrombocytopenia of unexplained nature. Thrombocytopenia in pregnancy deserves special consideration because of the possible consequences on the fetus.

What is the prophylactic agent of choice for HIV+ adults with mycobacterium avium complex?

The Bottom Line: Azithroymycin or clarithromycin appear to be the agent of choice for MAC infections.  Further studies are needed, especially direct comparison of these two therapies.

Reference: Uthman MM, Uthman OA, Yahaya I.  Interventions for the prevention of mycobacterium avium complex in adults and children with HIV.  Cochrane Database Syst Rev. 2013 Apr 30;4:CD007191.

Summary: This review evaluated the effects of different strategies for preventing MAC infection. The authors found evidence from placebo-controlled studies that patients treated with rifabutin, clarithromycin and azithromycin were less likely to develop a MAC infection. Both clarithromycin and azithromycin when administered as a single agent were more effective than rifabutin monotherapy. Similarly, the combination of rifabutin with clarithromycin or azithromycin were more effective than rifabutin alone. The combination of rifabutin and azithromycin was no more effective than azithromycin alone. In addition, the combination of clarithromycin and rifabutin was no more effective than clarithromycin alone. In terms of survival benefits, only clarithromycin demonstrated benefit over placebo. However, there is no evidence of survival differences between any monotherapy versus monotherapy and combination therapy versus any monotherapy. The combination therapy has been reported to be associated with higher adverse events than monotherapy.

What is the differential diagnosis for patients presenting with proctitis and a history of HIV infection?

Bottom line:  In patients presenting with proctitis and a history of HIV infection, a sexual history of a man who has sex with men suggests a risk for sexually-transmitted infections:   gonorrhea, herpes simplex, chlamydia, and syphilis (in descending order of incidence in this population).  Other infections, such as HSV and lymphogranuloma venerum (LGV) may occur more frequently in this population compared to men who have sex with men but are HIV negative.

Davis BT, Thiim M, Zukerberg LR. Case 2-2006 — A 31-Year-Old, HIV-Positive Man with Rectal Pain. N Engl J Med 2006; 354:284-289.
This case report reviews the process of prioritizing the differential diagnoses based on sexual history and HIV status and discusses the place of empirical therapy and what to do in the case of recurrence.

Bissessor M, et al. The etiology of infectious proctitis in men who have sex with men differs according to HIV status. Sex Transm Dis. 2013 Oct;40(10):768-70. doi: 10.1097/OLQ.0000000000000022.
Case series of 279 men who presented with proctitis (141 HIV+ and 138 HIV-) at a public STI clinic. Incidence of pathogens:

Pathogen Incidence in HIV+ pts Incidence in HIV- pts
Chlamydia 23.4% 21.7% (p=0.7)
Gonorrhea 13.4% 10.8% (p=0.5)
HSV-1 14.2% 6.5% (p=0.04)
HSV-2 22% 12.3% (p=0.03)
LGV 7.8% 0.7% (p=0.004)
multiple infections 17.7% 8.6% (0.017)