Neuroscience 101

It is in your head

Asthma: A simple concept but a complex heterogeneous disease

Asthma is a complex chronic syndrome in which inflammation of the airways is linked to variable degrees of airflow limitation and airway hyperactivity.

Several processes contribute to airflow limitation in asthma, including the following:

  • Bronchoconstriction, the intensity of which depends on the underlying airway inflammation,
  • Airway hyperresponsiveness, which is exaggerated by bronchoconstriction to a variety of stimuli,
  • Submucosal edema,
  • Mucous hypersecretion and plugging,
  • Structural changes in the airway itself, known as airway remodeling, that are associated with progressive loss of lung function.

Bronchial smooth muscle contracts in response to allergens and irritants. Airway edema and inflammation along with mucous hypersecretion, formation of mucous plugs, and airway remodeling further limit airflow as asthma becomes persistent and the inflammation becomes more severe. Inflammation is the major factor in the severity of airway hyperresponsiveness; airway remodeling and dysfunctional neuroregulation are other contributors. Activation of structural cells and permanent changes in the airway that obstruct airflow define airway remodeling. A more thorough discussion of airway remodeling is presented later in this chapter.

Numerous Mechanisms Converge to Promote Asthma

Our understanding of asthma as a heterogeneous disease is evolving. According to the most recent Expert Panel Report of the National Asthma Education and Prevention Program (2007), evidence has emerged for the existence of several different asthma phenotypes based on the observed variability of inflammation in patients with asthma. The heterogeneity in the pathophysiological processes that interact and are complicit in the development of asthma has important implications for treatment.

It is well recognized that many cellular elements play a role in the chronic airway inflammation that characterizes asthma: mast cells, eosinophils, T lymphocytes, macrophages, neutrophils, and epithelial cells. These inflammatory cells release mediators that trigger bronchoconstriction and promote airway remodeling. Inflammatory mediators include lymphocytes, mast cells, eosinophils, neutrophils, dendritic cells, macrophages, airway smooth muscle cells, and epithelial cells.

Of all types of asthma, allergic asthma is the most well defined with regards to immunopathogenesis. The antibody immunoglobulin E (IgE) activates allergic reactions and is involved in the development of inflammation and its persistence. The surfaces of mast cells contain large numbers of IgE receptors. When these receptors are activated by an antigen, they release mediators such as histamine and leukotrienes that stimulate acute bronchospasm. They also release proinflammatory cytokines that perpetuate underlying airway inflammation.

Two subpopulations of lymphocytes are helper T (TH) 1 cells and TH2 cells, each with distinct inflammatory mediator profiles and effects on airway function. An imbalance between the TH1 and TH2 arms of the immune system, in favor of the TH2 subtype, is thought to drive allergic inflammation: TH2 cells are essential for IgE production, and an imbalance of between TH1 and TH2 cytokines in favor of TH2 would result in overproduction of IgE. A shift in the TH cell population from TH1 to TH2 cells occurs with eosinophilic inflammation. Dendritic cells, which function as key antigen-presenting cells, interact with allergens from the airway surface and migrate to regional lymph nodes where they interact with naive T cells to stimulate production of TH2 cells.. TH2 cells release interleukin (IL)-5, a potent eosinophil chemoattractant that also regulates eosinophil behavior, including accumulation and activation in the lungs.

Consistent Pattern of Airway Inflammation

With the possible exception of pauci granulocytic asthma, airway inflammation is a consistent pattern across all asthma phenotypes. Bronchoscopic studies reveal abnormal histopathologic lesions and inflammatory cell infiltration in patients with asthma regardless of its severity.

The cause of airway inflammation is not simply excessive smooth muscle contraction. Interactions between neural mechanisms, inflammatory cells, inflammatory mediators, and abnormalities of smooth muscle cells have been described. A unifying defect to explain all of the abnormalities found in asthma is lacking, however, which complicates approaches to treatment. Furthermore, the nature of the basic pathogenesis has not been established. Although a genetic basis for airway hyperresponsiveness is suggested, asthma is not a single genetic abnormality but rather a complex multigenic disease with a strong environmental contribution.

The Link with Reactive Oxygen Species

The presence of specific biomarkers in expired air reflects an altered airway redox chemistry in patients with asthma. In particular, high levels of reactive oxygen species (ROS) — superoxide, hydrogen peroxide, and hydroxyl radicals — have been documented in asthmatic airways, and ROS levels increase during exacerbations of asthma. Activated pulmonary inflammatory cells (ie, eosinophils, alveolar macrophages, and neutrophils) in patients with asthma produce high levels of ROS. Increased production of neutrophils has been found to correlate with the severity of airways reactivity in patients with asthma, and neutrophilic airway infiltrates are found in patients with asthma.

Nitric oxide (NO) is another reactive species found in high quantity in the airways of asthmatics. Nitric oxide is produced by NO synthase, all isoforms of which are present in the lung.

New evidence points to the end products of NO consumption as a reliable marker of airway inflammation, with high levels despite corticosteroid treatment indicative of more severe asthma (the use of NO for inflammation monitoring will be discussed in more detail).

Airway Remodeling:
Features and Chronology 

In asthma, airway epithelial and mesenchymal cells respond abnormally to environmental injury. The repair response to insult is also compromised, inducing immunopathologic reactions in genetically susceptible individuals that may allow for greater access of inhaled allergens, irritants, and viruses to basal cells to induce inflammatory processes.

In the presence of asthma, the airway epithelium undergoes structural changes known as airway remodeling. Airway remodeling may be defined as persistent airflow obstruction despite aggressive anti-inflammatory therapies. Pathologic features of airway remodeling include an increase in smooth muscle mass, mucous gland hyperplasia, persistence of chronic inflammatory cellular infiltrates, release of fibrogenic growth factors along with collagen deposition, and elastolysis. Of these changes, basement membrane thickening is thought to be the earliest indicator of remodeling in asthma. Indeed, several studies have shown basement membrane thickening is already present even in children with mild asthma.

The normal epithelium serves a barrier function to ward off inhaled allergens and irritants to basal cells. Asthma is characterized by loss of epithelium and thickening of the basal membrane with the deposition of collagen. Thickening of the airway smooth muscle cell layer also occurs, as a result of hyperplasia and hypertrophy. At the same time, the number of mucus-secreting goblet cells in the epithelium increases, submucosal edema becomes prominent, and enhanced secretion of vascular endothelial growth factor contributes to an increase in vascularity, indicative of a chronically injured epithelium. The increased fragility of the epithelium leads to a loss of permeability and its barrier function, allowing greater access of inhaled irritants to the basal cells and underlying airway tissue. The damaged epithelium in asthma promotes the production of cytokines and growth factors as an impaired repair response. Epidermal growth factor also stimulates the damaged epithelium to secrete mucus, and infiltration of neutrophils and other inflammatory cells occurs as a result of an altered inflammatory response.

Pathologic features of airway remodeling
• Increase in smooth muscle mass
• Mucus gland hyperplasia
• Persistent chronic inflammatory infiltrates
• Release of fibrogenic growth factors
• Collagen deposition
• Elastocytosis

Respiratory viral infections represent another environmental insult that targets the airway epithelium. The damaged airway epithelium has difficulty eliminating these viruses and they continue to replicate and destroy epithelial cells, provoking the release of mediators.

Asthma Phenotypes

Four distinct asthma phenotypes have been described.  Multiple factors appear to account for the phenotypic differences in asthma, including differences in genetic background and exposure to environmental stimuli.

Eosinophilic Asthma

The role of eosinophils in airways dysfunction is controversial. Supporting a role for eosinophil involvement is the broad correlation between airway eosinophilia and asthma severity, the substantial reduction in eosinophil level in sputum and tissue with corticosteroid treatment, and the clinical improvement observed with this reduction in eosinophil number. Arguing against a role for eosinophils in the immunopathologic process is the lack of efficacy of an anti-IL-5 monoclonal antibody in reducing airway hyperresponsiveness or asthma symptoms. Regardless, the presence of eosinophils in the airways serves as a marker for steroid responsiveness.

Neutrophilic Asthma

As mentioned, the inflammatory process in asthma is heterogeneous, and includes noneosinophilic forms of asthma. A subset of patients with asthma lack eosinophils in the airways but instead have an increased number of neutrophils. Active neutrophil elastase is a feature of asthma with neutrophilic inflammation, whereas eosinophilic asthma is characterized by active matrix metalloproteinase (MMP-9) without free elastase. Neutrophils in the sputum signal aggressive asthma that is associated with higher degrees of airway remodeling. The role of neutrophils in the pathophysiology of asthma remains unknown but their presence appears to be a marker for asthma that is refractory to steroid therapy.

Paucigranulocytic Asthma

Paucigranulocytic asthma is asthma in the absence of eosinophils and neutrophils, with normal levels of the proteolytic enzymes MMP-9 and neutrophil elastase in sputum. The levels of these two proteolytic enzymes are typically increased in asthma and are important mediators of tissue remodeling and repair. Because the levels of these enzymes are normal in paucigranulocytic asthma, there may be abnormal airway epithelium, or the underlying smooth muscle may itself lead to the development of the asthmatic phenotype without the presence or development of obvious inflammation.

Steroid-Refractory Asthma

Resistance to corticosteroid therapy represents another asthma phenotype. Although the exact mechanism of steroid resistance remains unknown, recent experimental evidence suggests that TH17 cells act as mediators of steroid-resistant airway inflammation.

Summary

A confluence of cellular events is responsible for the airway inflammation and hyperresponsiveness and the airflow obstruction that characterize asthma. The airway epithelium itself is complicit in the pathogenesis of asthma, as it is known to activate dendritic cells. Distinct asthma phenotypes support the presence of separate but overlapping syndromes that make up asthma.

Severe Asthma:
Definitions and Characteristics

It is estimated that up to 15% of patients with asthma have severe disease or disease refractory to typical treatments, including systemic corticosteroids. The Epidemiology and Natural History: Outcomes and Treatment Regimens (TENOR) study, a prospective, observational, multicenter study of 4,756 patients with severe/difficult-to-control asthma, revealed for the first time the disabling high level of health care resource utilization by this patient population, including emergency room visits, medications, and hospitalizations. Among the unexpected findings of the study, up to 60% of TENOR participants required an oral corticosteroid burst, 20% had an emergency department visit, and 10% had to be hospitalized. Consistent with these findings, Cisternas et al found that total per-person costs were $12,813 for patients self-reporting severe asthma, more than double the costs associated with moderate asthma ($4,530) and five times the costs associated with mild asthma ($2,646).

Definitions of Asthma Severity

In order to manage asthma most effectively, an accurate assessment of asthma severity is essential. Validated survey instruments are useful to evaluate asthma control and quality of life. The American Thoracic Society (ATS) and the European Network for Understanding Mechanisms of Severe Asthma (ENFUMOSA) have provided criteria-based definitions for severe asthma, among which corticosteroid use is a major factor in determination of severity. Recent studies by the Severe Asthma Research Program (SARP) funded by the National Heart Lung and Blood Institute (NHLBI) have provided a unique classification of phenotypes of severe asthma on the basis of cluster analyses.

The standard classification of all asthma recommended for clinical care is provided by the NHLBI National Asthma Education and Prevention Program (NAEPP) Expert Panel Reports. The 2007 Third Expert Panel Report of the NAEPP comprehensively updated classifications for asthma severity and control and provided guidelines for treatment approaches based on classification. NAEPP classifications range from mild intermittent asthma to severe persistent asthma, primarily based on history of asthma symptoms and lung functions. Similar to prior NAEPP guidelines, the Third Expert Panel Report recommends a stepwise approach to treatment based on asthma severity, and once therapy is initiated, clinical management decisions should be based on asthma control.

Although the NAEPP guidelines identify a severe persistent asthma category, this grouping does not identify those patients with poorly controlled or refractory asthma. Specifically, some patients with asthma have frequent and severe symptoms despite intense acute and long-term therapy. The difficulty of assessing asthma severity is exemplified by Miller et al,  who compared three different approaches to asthma severity classification: the NAEPP classification system; criteria used by the Global Initiative for Asthma (GINA) guidelines, which are joint NHLBI and World Health Organization (WHO) recommendations similar to NAEPP; and physician assessment (professional judgment; criteria not specified). Considerable disagreement in asthma classification was observed among the three approaches. Many of those classified as mild by NAEPP criteria were rated as moderate or severe by physician assessment. Furthermore, health care resource use was out of proportion to the severity of asthma in a large percentage of patients classified as mild by NAEPP criteria.

American Thoracic Society (ATS): Severe Asthma Definition

The ATS workshop consensus for the definition of severe/refractory asthma (published in 2000) requires satisfaction of one major criterion—treatment with continuous or near continuous oral corticosteroids and/or treatment with high-dose inhaled corticosteroids—and at least two minor criteria from a list of eight that includes aspects of lung function, disease stability, exacerbations, and use of additional controller medications. The ATS criteria provide both a uniform metric for defining severe asthma and a reproducible definition of severe asthma for studies. More importantly, they enable practitioners to investigate this at-risk population and to provide improved care.

American Thoracic Society workshop: definition of severe/refractory asthma
At least one major criterion must be met

  • To achieve control to level of mild to moderate persistent asthma:
    • Treatment with oral corticosteroids at least 50% of the year
    • Treatment with high-dose inhaled corticosteroids
And
At least two minor criteria must be met

  • Requirement for additional daily treatment with second controller medication
  • Symptoms require treatment with daily short-acting beta-2 agonist
  • Persistent airflow obstruction, as defined by FEV1 < 80% predicted or diurnal PEF variability > 20%
  • One or more urgent care visits for asthma per year
  • Three or more oral steroid “bursts” per year
  • Prompt deterioration with a 25% or less reduction in corticosteroid dose (inhaled or oral)
  • Near-fatal asthma event in the past

FEV1 = forced expiratory volume in 1 second; PEF = peak expiratory flow

Characterizing Severe Asthma:
Findings From Investigations Of
Populations With Severe Asthma

European Network for Understanding Mechanisms of Severe Asthma

(ENFUMOSA)

The ENFUMOSA study, a multinational project to investigate the clinical characteristics and physiologic mechanisms of severe asthma, identified characteristics of patients with chronic severe asthma. Those with severe asthma were predominantly female, less likely to have allergies, and more likely to have aspirin intolerance; they also had greater asthma exacerbations in the autumn months. Exacerbations in men with severe asthma were associated with higher levels of stress and anxiety; in women with severe asthma, exacerbations tended to occur premenstrually.

European Network for Understanding Mechanisms of Severe Asthma: Definition of severe asthma
Patient must meet at least three of the following criteria:
• Under the care of a consultant in asthma for at least 2 years
• Persistent symptoms and quality of life impairment
• Receipt of maximal usual asthma therapy and/or medications (high doses of inhaled corticosteroids) and documented adherence to therapy
• Previous respiratory failure/intubation/near-fatal episodes
• Repeated FEV1 < 70% predicted

FEV1 = forced expiratory volume in 1 second

The subgroup of patients in ENFUMOSA who had chronic severe asthma demonstrated pulmonary dysfunction that was resistant to bronchodilators, elevated neutrophil levels in sputum and blood, elevated nitric oxide (NO) levels, and increased excretion of eosinophil peroxidase and leukotriene E4. Eosinophils and neutrophils persisted in sputum in the patients with severe asthma despite high doses of inhaled or systemic corticosteroids.

Severe Asthma Research Program (SARP)

The NHLBI-funded SARP has the largest cohort of patients with severe asthma, as defined by ATS criteria. Studies of the SARP cohort confirmed the persistence of symptoms and high health care resource use in patients with severe asthma despite complex medication regimens that included high doses of inhaled or oral corticosteroids. Phenotypic characterization of SARP participants revealed that patients with severe asthma in SARP were likely to have a history of sinopulmonary infections, persistent symptoms, and significant nonrespiratory comorbidities leading to high health care utilization.

Severe Asthma Phenotypes

A cluster analysis of the SARP population identified five distinct asthma clusters based on lung function, age of asthma onset and duration, atopy, gender, symptoms, medication use, and health care resource use, revealing the heterogeneity of the disease. One-third of SARP patients were grouped into clusters 4 and 5, which appear to be the most severe clusters. Features characteristic of patients in these clusters were a long duration of asthma, severe airflow limitation at baseline, abnormal lung function despite the use of multiple asthma medications, frequent treatment with systemic corticosteroids, high health care resource use, prior admissions to the intensive care unit for asthma, daily symptoms, and poor quality of life.

Table 4: Asthma cluster analysis
Group
Diagnosis Characteristics
1
Mild allergic asthma
N = 110
Early onset asthma, 80% female
Normal lung function
≤2 controllers, minimal health care utilization
2
Mild-moderate allergic exacerbating asthma
N = 321
Most common cluster, early onset asthma, 67% female
Borderline normal FEV1 but reverses to normal
≤2 controllers, very low health care utilization, but some
steroid bursts
3
Moderate to severe older-onset asthma
N = 59
Older, late onset asthma; higher BMI, 71% female, less
atopic
Moderate decrease in FEV1, some reversibility
On higher ICS; ≤3 controllers, but despite this more
OCS bursts
4
Severe variable allergic asthma
N = 120
Young, early onset asthma, 53% female
Severely decreased FEV1, but reversible to near normal
OCS “variable” with need for frequent steroid bursts
5
Severe fixed airflow asthma (“COPD similarities”)
N = 116
Older, late onset asthma (longest duration), 63% female,
less atopic
Severely decreased FEV1, more fixed, less reversibility
On OCS, higher BMI, more gastroesophageal reflux
disease and hypertension, high health care utilization

FEV1 = forced expiratory volume in 1 second; BMI = body mass index; OCS = oral corticosteroids; ICS = inhaled corticosteroid.

Assessing the Risk of Adverse Events in Severe Asthma

Patients with severe asthma are at risk for adverse events including fatal and near-fatal asthma. Assessment of risk for life-threatening events is a priority in studying patients with severe asthma. The test used most often to predict risk is spirometry, especially forced expiratory volume in 1 second (FEV1). Although a decline in FEV1 contributes to greater asthma severity, additional factors are probably required for disease progression, including progressive inflammation hyperresponsiveness, worsening lung compliance, or a greater symptom burden. The need for more accurate tests that correlate with the severity of risk has led to the study of inflammatory biomarkers.

Measurements of fractional nitric oxide (NO) concentration in expired breath (FENO) is a quantitative, noninvasive, simple, and safe test to determine airway inflammation. FENO levels were similar among patients with severe and nonsevere asthma in SARP, in contrast to the patients with severe asthma in ENFUMOSA. However, high levels of FENO identified those patients with the greatest airflow obstruction and hyperinflation and most frequent use of emergency care. Thus, grouping patients with severe asthma by FENO level may identify those patients with the most reactive and worrisome asthma phenotype.   Monitoring FENO may be used to measure lower airway inflammation, monitor the efficacy of anti-inflammatory therapy, and monitor disease activity.

Treatment Options for Severe Asthma

Treatments for severe persistent asthma are limited and consist mainly of high doses of inhaled corticosteroids and inhaled long-acting beta-2 agonists. Adherence to these regimens is difficult, the response to them is variable, and side effects can be serious. Safer and more effective therapies for severe asthma are needed.

Treatment Based on Level of Disease Severity

As with previous guidelines issued by the National Asthma Education Prevention Program (NAEPP), the 2007 update recommends a stepwise approach for the management of asthma based on the level of severity. A treatment algorithm consisting of six steps was proposed, starting with short-acting beta-2 agonists (step 1) and gradually increasing the intensity of treatment to include, in step 6, combinations of high-dose inhaled corticosteroids, long-acting beta-2 agonists , and short-term “bursts” of oral corticosteroids. The guidelines recommend starting treatment of severe asthma with steps 4 or 5 — medium- to high-dose inhaled corticosteroids and long-acting beta-2 agonists, with consideration given to a leukotriene modifiers and, for patients who have allergies, omalizumab.

Drug therapy for severe asthma
Medication Therapeutic issues
Inhaled corticosteroids In severe asthma, combining low-dose inhaled corticosteroids with LABAs may achieve greater benefit than using a high-dose corticosteroid regimen
Systemic corticosteroids For long-term prevention of symptoms in severe persistent asthma; alternate-day morning dosing minimizes toxicity
Inhaled LABAs Should be used only with inhaled corticosteroids; the combination synergistically improves control
Leukotriene modifiers A trial with an antileukotriene agent (ie, montelukast or zafirlukast) might benefit patients with severe asthma who are uncontrolled on inhaled corticosteroids and LABA; if an antileukotriene does not achieve asthma control within 3 months, the 5-lipoxygenase inhibitor zileuton can be tried as an alternative
Omalizumab Shown to decrease need for corticosteroids and to improve quality of life; for use only in patients with documented allergy and elevated IgE; monitor after administration for possible anaphylaxis

IgE = immunoglobulin E; LABA = long-acting beta-2 agonist.

Daily maintenance therapy is suggested for persistent disease. The NAEPP guidelines emphasize the presence of chronic airway inflammation as a central feature in all patients with asthma regardless of the precise pathogenesis; accordingly, inhaled corticosteroids are first-line therapy for all patients with persistent asthma.

Corticosteroids

Corticosteroids suppress inflammation by reversing histone acetylation of activated inflammatory genes through binding of glucocorticoid receptors to coactivators and by inducing the recruitment of the nuclear enzyme histone deacetylase 2 (HDAC2) to multiple activated inflammatory genes. The poor response to corticosteroids observed in patients with severe asthma may reflect a reduction in HDAC2 levels and its function. Corticosteroids do not reverse airway remodeling, which may partially explain continuation of some symptoms despite treatment.

The use of more potent inhaled corticosteroids at higher doses, especially for more severe asthma, was predicated on the hypothesis that a dose-response effect exists for these agents. At least in patients with moderate persistent asthma who remain symptomatic on low-dose inhaled corticosteroid monotherapy, evidence indicates that a greater benefit may be achieved by adding a long-acting inhaled bronchodilator rather than doubling the dose of inhaled steroid. The relative benefit of this approach compared with high-dose inhaled corticosteroids in patients with severe asthma is unknown.

Corticosteroid Resistance

A small proportion of patients fail to respond even to high-dose corticosteroids. Two types of relative steroid resistance have been described:

  • Type 1 steroid resistance is a relative lack of steroid responsiveness in the airways, although the steroid effect is evident in other tissues of the body, usually manifesting as clinical steroid side effects (ie, cushingoid effects). Type 1 steroid resistance is acquired and is the more common of the two types.
  • Type 2 steroid resistance has a genetic basis and is caused by a generalized lack of steroid responsiveness in the airways and other organ systems. Patients with type 2 resistance have poor asthma control despite systemic corticosteroids and no systemic steroid side effects. Type 2 steroid resistance is rare.

The relative contribution of steroid resistance in suboptimal asthma control remains unknown. Patients with a molecular basis for steroid resistance may be a subset who would benefit from alternative anti-inflammatory approaches.

Alternatives and Add-ons to Steroids

Alternatives to high-dose systemic steroids and their potential side effects in patients with poor steroid responsiveness are few.

Long-Acting Beta-2 Agonists

Long-acting beta-2 agonists may be less beneficial in patients with severe asthma compared to those with moderate, persistent asthma. The combination of inhaled corticosteroids and long-acting beta-2 agonists synergistically improves asthma control, although the molecular mechanism behind such a synergy is not fully known. Beta-2 agonists may facilitate the steroid effect whereas the steroids upregulate the beta-2 agonist receptors. New US Food and Drug Administration recommendations suggest that these drugs should not be used without corticosteroids or some other asthma controller medication. When asthma control is ensured, it is recommended that these agents be discontinued because of the risk of rare cardiovascular events.

Leukotriene Modifiers

The role of antileukotriene agents in the management of asthma is primarily in chronic mild to moderate asthma, although the addition of an antileukotriene agent may permit tapering of inhaled corticosteroids in patients with more severe forms of asthma who require moderate to high doses of inhaled steroids. Leukotriene modifiers may be beneficial in patients with severe asthma who are aspirin sensitive.

Immunotherapy

Immunoglobulin E (IgE) increases allergen uptake by dendritic cells and activates mast cells and basophils for mediators. Omalizumab is a humanized immunoglobulin G1 (IgG1) antibody that reduces the amount of free IgE available to bind to FceRI receptors on mast cells, basophils, and other cells. Omalizumab administration requires proven elevation of IgE (30 IU/mL to 700 IU/mL) and a positive skin test or in vitro reactivity to a perennial allergen.

Subcutaneous administration of omalizumab every 2 to 4 weeks has been shown to improve symptom control and allow for a reduction in the dosage of inhaled corticosteroids. Although anti-IgE therapy has been shown to reduce the rate of hospitalization in patients with moderate to severe allergic asthma, its utility in very severe asthma has not been established.

In a large, placebo-controlled study in patients with moderate to severe perennial allergic asthma, a 50% or greater reduction in dosage of oral corticosteroids was reported in 78% of subjects receiving 5.8 mg/kg/ng IgE/mL of omalizumab and in 57% of those receiving a lower dose (2.5 mg/kg/ng IgE/mL), which was significant compared with 33% of subjects in the placebo group (P = 0.04). More than one-third of patients assigned to omalizumab were able to discontinue oral corticosteroids. One-fifth of the patients taking inhaled corticosteroids were able to completely discontinue steroid use after being treated with omalizumab.

More recent studies have confirmed that in properly selected patients with severe persistent asthma that is poorly controlled despite use of combination controller therapy, omalizumab is efficacious for reducing exacerbations over time and improving quality of life.

Immunosuppressives and Other Alternatives

Older nonspecific, systemic, alternative anti-inflammatory agents (methotrexate, gold, cyclosporine) have significant and unacceptable side effects and, therefore, are not used to treat asthma.

Investigational Pharmacologic Approaches

Anticytokine Therapies

Several early-phase human studies have been conducted with pharmacologic
agents that antagonize the interleukin (IL)-4, IL-5, and IL-13 pathways involved in eosinophilia and asthmatic airway inflammation, with mixed results.

An intravenous humanized monoclonal antibody to IL-5 was disappointing in a double-blind, placebo-controlled trial using an inhaled allergen-challenge model. Even though a single intravenous dose of anti-IL-5 decreased blood eosinophilia for 16 weeks and sputum eosinophilia for 4 weeks, there was no significant effect on the late asthmatic response or airway hyperresponsiveness to allergen challenge.

Several studies with an inhaled soluble IL-4 receptor antagonist, altrakincept, found modest improvement in symptom scores and forced expiratory volume at 1 second (FEV1) but without an effect on the rate of asthma exacerbation.  Further development of altrakincept was discontinued by the manufacturer.

Novel Steroids

Various approaches to maximize the local activity of systemic or inhaled steroids within the airways, while minimizing systemic absorption and toxicity, are being pursued. Agents undergoing clinical trials include the following:

    • “On-site-activated steroids” such as ciclesonide, which is a nonhalogenated inhaled corticosteroid prodrug that requires endogenous cleavage by esterases for activity;
    • “Soft steroids,” which have improved local, topical selectivity and much less steroid effect outside the target area;
  • “Dissociated steroids,” or agents that favor monomeric glucocorticoid receptor complexes (ie, they produce “transrepression”) and avoid dimerization or “transactivation,” which is undesirable in asthma.

Bronchial Thermoplasty

Airway smooth muscle mass is increased in patients with asthma, and the degree of smooth muscle hyperplasia correlates with disease severity. Airway hyperresponsiveness may arise from an abnormality of airway smooth muscle. Contraction of smooth muscle leads to airway narrowing and airflow obstruction.

Bronchial thermoplasty uses controlled radiofrequency-generated thermal energy applied directly against the airway wall through a bronchoscope to reduce excessive airway smooth muscle massA complete course requires three procedures over 6 weeks (ie, 3 weeks between procedures).

The rationale for this new procedure is that by reducing this smooth muscle, bronchial thermoplasty can reduce bronchial reactivity and the propensity for smooth muscle-mediated bronchoconstriction, thereby reduces the symptoms of asthma, limiting asthma exacerbations, and improving asthma control and quality of life. The mechanisms of effect, however, are not clear.

In 2010, the FDA approved bronchial thermoplasty for the treatment of severe, persistent asthma in patients 18 years and older.

Clinical Trial Results

An early randomized clinical study in 112 patients with poorly controlled asthma despite therapy with inhaled corticosteroids and long-acting beta-2 agonists showed a 53% reduction in the rate of mild exacerbations compared with controls during the first year after bronchial thermoplasty (P =.005). Table shows secondary endpoint results.

Secondary endpoints in AIR1 trial; 12-month changes from baseline.
Endpoint Bronchial thermoplasty Control P value
Asthma Quality of Life Questionnaire (reductions) 1.3 0.6 .003
Asthma Control Questionnaire (reductions) 1.2 0.5 .001
Symptom-free days (%) 40.6 17.0 .005
Symptom scores (reductions) 1.9 0.7 .01
Morning peak expiratory flow liters/min 39.3 8.5 .003
Use of rescue medications (reductions) puffs/wk 1.1 4.0 .04
Prebronchodilator (% predicted, increase) forced expiratory volume in 1 second 5.0 1.0 NS
Airway responsiveness NS

Pavord et al demonstrated a significant reduction in the use of rescue medication through 52 weeks and a trend toward ability to be weaned off steroids among patients with symptomatic severe asthma randomly assigned to bronchial thermoplasty compared with controls.

In the Asthma Intervention Research 2 (AIR2), bronchial thermoplasty was compared with a sham procedure in 288 patients with severe asthma who were symptomatic despite treatment with high-dose inhaled corticosteroids and long-acting beta-2 agonists. Compared with patients undergoing the sham procedure, treated patients had fewer health care utilization events, such as the following:

  • A 32% reduction in the number of asthma attacks;
  • An 84% reduction in emergency room visits for respiratory symptoms;
  • A 66% reduction in days lost from work/school or other activities because of respiratory symptoms.

Approximately 80% of bronchial thermoplasty-treated patients had clinically significant improvements in scores on the Asthma Quality of Life Questionnaire versus 64% of sham controls; 36% fewer treated patients reported episodes of asthma adverse events.

Short-term risks of bronchial thermoplasty are respiratory adverse events related to transient worsening of asthma. These typically occur within 1 day and resolve within 1 week with standard care. In AIR2, respiratory adverse events during the treatment phase occurred in 85% of bronchial thermoplasty-treated patients compared with 76% of sham controls. This trend reversed in the 12 to 52 weeks after treatment, in which the rates of respiratory events were 70% in patients randomized to bronchial thermoplasty and 80% of those randomized to sham bronchoscopy. Severe adverse events occurred in 3% of treated patients, the most significant of which was hemoptysis treated with embolization.

Contraindications in clinical trials were life-threatening asthma; chronic sinus disease; respiratory diseases such as emphysema; use of immunosuppressants, beta-adrenergic blocking agents, or anticoagulants; and history in the previous year of three or more hospitalizations for asthma, three or more lower respiratory tract infections, and four or more pulses of oral corticosteroids for asthma.

Migraineurs: Get to know your buddy, migraine, thoroughly.

For a simplified post, visit: http://neurologyfordummies.com/2010/09/15/i-have-a-migraine/

Understanding Migraine — in an excessively exhaustive manner

Migraine is a primary episodic headache disorder and can occur with various combinations of neurological, gastrointestinal and autonomic changes.

International Headache Classification of Headache.

Migraine

  • 1.1 Migraine without aura
  • 1.2 Migraine with aura
    • 1.2.1. Typical aura with migraine headache
    • 1.2.2. Typical aura with non-migraine headache
    • 1.2.3. Typical aura without headache
    • 1.2.4. Familial hemiplegic migraine
    • 1.2.5. Sporadic hemiplegic migraine
    • 1.2.6. basilar-type migraine
  • 1.3 Childhood periodic syndromes that are commonly precursors of migraine
    • 1.3.1. Cyclical vomiting
    • 1.3.2. Abdominal migraine
    • 1.3.3. Benign paroxysmal vertigo of childhood
  • 1.4. Retinal migraine
  • 1.5. Complications of migraine
    • 1.5.1. Chronic migraine
    • 1.5.2. Status migrainosus
    • 1.5.3. Persistent aura without migraine
    • 1.5.4. Migrainous infarction
    • 1.5.5. Migraine-triggered seizures
  • 1.6. Probable migraine
    • 1.6.1. Probable migraine without aura
    • 1.6.2. Probable migraine with aura

The migraine attack can consist of premonitory aura, headache and resolution phases.

Our focus in this post will be on migraine and migraine with aura. Because of their frequency of clinical presentation and characteristics that can resemble aspects of migraine, I will also include two other headache subtypes: brief, recurrent, localized pain, i.e., cluster headache and long-lasting, continuous, more generalized pain, i.e., idiopathic low-cerebrospinal fluid (CSF) pressure headache. Finally, I will discuss migraine comorbid conditions (depression and anxiety) and their common impact on migraine care.

The International Headache Society (IHS) divides migraine into with and without aura subtypes. Migraine is defined as: (A) at least five attacks of head pain; (B) with headache episodes lasting 4-72 hours (untreated or unsuccessfully treated) and (C) pain described as having at least two of the following characteristics � unilateral origin, pulsating nature, of moderate or severe intensity and aggravated by routine physical activity (i.e., walking or climbing stairs). In addition (D) during the headache, at least one of the following symptoms occurs – nausea and/or vomiting, photophobia and phonophobia. No single feature is mandatory but recurrent episodes must be documented. Finally (E), the head pain cannot be attributed to another disorder.

Diagnostic Criteria for Migraine (-without and -with Aura)

1.1 Migraine without aura

  1. At least five attacks fulfilling B-D
  2. Headache attacks lasting 4-72 h (untreated or unsuccessfully treated)
  3. Headache has at least two of the following characteristic
    • Unilateral location
    • Pulsating quality
    • Moderate or severe intensity (inhibits or prohibits daily activities)
    • Aggravation by walking stairs or similar routine physical activity
  4. During headache at least one of the following:
    • Nausea and/or vomiting
    • Photophobia and phonophobia
  5. Not attributed to another disorder

1.2. Migraine with aura

  1. At least two attacks fulfilling B-D (from 1.1)
  2. Fully reversible visual, sensory, or aphasic aura symptoms (but no motor weakness)
  3. At least two of the following:
    • Homonymous positive features and/or unilateral sensory symptoms
    • ≥1 symptom develops gradually over >5 min or >2 occur in succession
    • Each symptom lasts 5-60 min
  4. Headache follows aura with a free interval of <60 min (or it may also begin before or simultaneously with the aura)
  5. Not attributed to another disorder

Migraine with aura, in addition to the above characteristics, must show evidence of being fully reversible, defined as at least two fully reversible visual, sensory or language symptoms that precede or accompany the appearance of migraine-like headache. Migraine with aura is subdivided into typical aura, prolonged aura, hemiplegic migraine, basilar-type migraine and migraine with acute onset aura. The IHS classification now allows the association of aura with other headache types. Prolonged aura lasts from one hour to one week; persistent aura lasts for greater than one week (but resolves); if neuroimaging demonstrates a stroke, a migrainous infarction has occurred. Migraine persisting for three or more days defines “status migrainosus.”

Pharmacotherapy for migraine may be acute (abortive) or preventive (prophylactic). Patients may require both approaches. Acute treatment attempts to reverse or stop the progression of a headache once it has started. Preventive therapy is designed to reduce attack frequency and severity. Acute treatment can be specific (i.e., ergots and triptans) or nonspecific (i.e., analgesics and opioids). Nonspecific medications control the migraine pain or other pain disorders, while specific medications are effective in migraine (and certain other) headache attacks but are not useful for non-headache pain disorders. Triptans are effective in the range of mild, moderate and severe migraine attacks. Patients with moderate or severe headaches with moderate or severe disability  who were stratified to a triptan did better than patients given aspirin and metoclopramide. Abortive therapy alone is appropriate when headaches are relatively infrequent (i.e., ≤4/month). When headache frequency surpasses this rate (or individual headaches last for several days of the month, prophylactic therapy is indicated as the primary pharmacological means to reduce headache attacks.

The mechanisms for effective abortive and prophylactic pharmacological treatments remain incompletely defined, as are the pathophysiological bases for migraine aura and pain. However, considerable evidence indicates that spreading depression (SD) is the underlying cause, not only of migraine aura but also of migraine pain. SD is a unique and non-injurious activation of brain with three defining electrophysiological characteristics: (1) a slowing (i.e., 3-5 mm/min) propagating wave of (2) electrical silence and (3) pronounced (i.e., several mV) negative DC shift in involved brain interstitial space. The unique hallmark of SD is its slowly propagating nature. No other electrophysiological brain process moves at this rate. Remarkably, Lashley first noted this slow rate of progress by clocking the estimated speed of his own visual scotoma across the visual cortex in 1941.

Propagation of Lashley's Scintillating Scotoma.

Top images show Lashley’s scintillating scotoma (red) as it moved from his central [with visual fixation point (green) as a reference spot] to peripheral visual field over 22 minutes. Lashley reasoned that this visual change must be represented in primary visual cortex, an expanse of about 67 mm (yellow arrow on sagittal MRI image], thus, a propagation speed of 3 mm/min!

SD occurs in gray matter areas of sufficient synaptic density (including neocortex and hippocampus) to support the phenomenon. Hippocampus is the brain structure most susceptible to SD and human hippocampus is known to sustain SD. Figure 2 illustrates the slowly propagating DC wave of SD as it travels over hippocampus grown in organotypic culture.

SD Propagation in Culture Hippocampal Slice.

The green to black wave is generated by a fluorescent, voltage sensitive dye that glows green when brain cells are polarized and shows no fluorescence (i.e., black) as cells depolarize from SD. For reference, the image to the right shows the representative cytoarchitecture of the pyramidal neurons (marked for the CA1 and CA3 areas) with the two black circles indicating the bipolar electrical stimulating electrode used to trigger the SD.

Belousov-Zhabotinsky Reaction in Petri Dish Resembles "Reaction-Diffusion" of Spreading Depression.

The slow spread of SD at 3-5 mm/min matches the propagation velocity of wave fronts in the Belousov-Zhabotinsky (BZ) reaction, a non-equilibrium thermodynamic reaction that can establish a non-linear chemical oscillator in an excitable milieu.

The latter, like brain, exists as a homogenous milieu of potentially excitable elements (i.e., chemical reactants and gray matter synaptic elements, respectively). Once triggered from a locus far from equilibrium (black dots) involving a sufficient synchronously active volume, reaction-diffusion process ensues as the BZ reaction, or in the case of brain, SD.

The triggering process for SD has recently been defined using current source density analyses (i.e., measuring net inward and outward currents across neuronal membranes) in hippocampal organotypic cultures. These cultures closely resemble normal brain but, unlike normal brain, the behavior of brain cells and tissue can be closely followed in space and time.

SD, like an epileptic seizure, begins with a flurry of increased neuronal activity. However, unlike an epileptic seizure, which spreads to asynchronously activate adjacent brain, SD begins with a synchronously activated brain space that is approximately 400 microns on a side. Within this volume, normal activation of the principle neurons of the hippocampus is briefly reversed. The cartoons illustrate pyramidal neurons (yellow) oriented with axons (A), dendrites (D), soma (S), dendrites (D) and axons (A) from top to bottom as the typical basilar to apical dendritic pattern seen in hippocampus. Under normal conditions, pyramidal neuron currents [inward (blue) and outward (red)] show typical excitatory (E), inhibitory (I), excitatory, inhibitory distribution moving from dendrites to soma (NL). The dendritic inhibition is “phasic” and the somatic inhibition “tonic.” Then, upon triggering SD, the somatic, tonic inhibition is reversed and becomes a strong inward current (blue), accompanied by outward currents (red) through the basilar dendrites (SDT). This electrogenic trigger initiates a reaction-diffusion process that is fueled by massive but transient degradation of ion gradients that occurs with associated release of neuroactive substances (e.g., neurotransmitters) (SDR/D). The latter involves cellular depolarization (and an associated large negative DC shift of the interstitial space), which means that traditional synaptic function is transiently lost (white lines) before neural tissue completely recovers. Next up is to define the ionic species responsible for the inward and outward currents that trigger SD as well as those responsible for its spread.

Hippocampal Pyramidal Neuron Currents of Spreading Depression.

The flurry of neuronal activity (i.e., bursting) seen at the beginning of SD is reminiscent of the onset of seizures except that, with SD, the volume of synchronously active tissue is likely to be considerably larger — and so establishes the “chemical oscillator” of SD. Notably, both involve increased synaptic currents, which may account for the progressive efficacy (i.e., adaptive protection) of anticonvulsant medications that inhibit SD and also migraine.

SD is commonly accepted as the basis for migraine aura. However, experimental studies show that SD is also a sufficient neural stimulus for nociceptive activation of the trigeminal nucleus. Thus, SD may also be responsible for the pain of migraine. Animal experiments of SD in the neocortex and hippocampus support this contention. The impact of triptans in aborting migraine aura and pain likely stems from effects to the trigeminal sensory system — including afferents at the pial surface where activation from SD can occur by simple diffusion (i.e., paracrine signaling) generated by the massive interstitial changes of SD. Activation of these meningeal trigeminal afferents are also likely to be responsible for the more global pain of low CSF pressure headaches. The bases for cluster headache pain remain unknown.

Region-specific blood flow reductions that last hours are found in migraineurs with aura.  Less frequently, oligemia develops in patients without aura.   Rarely, such changes fall more than 30-40% below normal.  Oligemia is consistent with the blood flow response induced by SD but the cause is unknown in migraine without aura, though SD is a logical suspect since animal studies show that SD transiently alters blood flow.

Changes in cerebral blood flow have been reported in migraine, particularly migraine with aura. For example, hemoglobin is diamagnetic when oxygenated and paramagnetic when it is deoxygenated. Furthermore, blood flow most often changes with neural activity. Therefore, blood flow changes proportionate to neural activation can be measured with magnetic resonance imaging of blood using BOLD (blood-oxygen-level) contrast. BOLD imaging during the aura phase of migraine shows a brief period of hyperperfusion followed by hypoperfusion of longer lasting duration. The hyperperfusion propagates at 3-5 mm per min along the calcarine cortex at a rate consistent with SD in experimental animals. Eight characteristics of SD were identified in the BOLD imaging study during migraine visual aura. Moreover, the retinotopy of the visual percept (visual aura) was congruent with the location of voxels showing a perturbation in the BOLD signal.

Blood flow changes are more variable with migraine without aura but the precise timing of those measurements to headache onset is often not precise. The most dramatic flow abnormalities were reported in a patient by Woods, Iacobini and Mazziotta who observed propagating hypoperfusion in the occipital lobe during a migraine attack without aura. The patient developed a severe headache in the absence of visual distortion or aura.

SD spreads at the rate of 3-5 mm/min and is a characteristic of all mammalian cortices.  The posterior pole of primary visual cortex is retinotopically related to central vision, whereas more peripheral vision is encoded within neurons more anteriorly along the calcarine sulcus.

Occasionally, migraine with aura patients experience hemiparesis. This neurological change heralds the migraine attack in susceptible patients and can be sustained for hours. With a family history of hemiparetic attacks, this patient may have “Familial Hemiplegic Migraine” (FHM). Three subtypes of FHM have been identified which involve a mutation-induced disturbance in ion channel flux or ion pumps. The ion channel mutations identified to date include point mutations in protein subunits affecting cation transfer or flux and include sodium, calcium and potassium. FHM1 is caused by point mutations in the CACNA1A gene encoding the alpha1-1 subunit of the P/Q calcium channel. This channel recognizes voltages changes and responds by opening upon depolarization, allowing calcium influx. The excitatory transmitter glutamate is released upon calcium influx. FHM-2 is caused by point mutations (28 different mutations identified to date) in a key protein subunit of the enzyme sodium potassium adenosine triphosphatase (i.e., Na/K ATPase). This critical pump subunit binds ATP, sodium, potassium, as well as digitalis-like drugs.

P/Q type calcium channels are abundantly expressed at presynaptic nerve endings of glutamatergic neurons.  In this location, the channel senses voltage fluctuations (e.g., depolarization) and, in response, changes its conformation to permit calcium entry into the presynaptic terminal.  Calcium entry into this compartment promotes glutamate release.  Mutation in a critical subunit of this heteropentameric complex (i.e., 5 subunit proteins) causes the channel to open for longer periods of time during small depolarizations, as well as during action potentials.  It, thereby, facilitates excessive glutamate release.  Glutamate is a key molecule implicated in the initiation of SD (i.e., preponderance of excitation compared to inhibition).

By virtue of its pumping action, Na/K ATPase regulates cellular ionic gradients.  The latter is required to maintain the resting membrane potential, power uptake of amino acids and regulate osmotic pressure within cells.  Reduced sodium pump activity has been implicated in FHM-2 and predisposes to SD, presumably by raising extracellular potassium levels.

Astrocytes take up glutamate and potassium from the synaptic cleft.  They are also positioned to provide a link between blood flow and synaptic activity.  They significantly outnumber neurons in the brain, are star-shaped (hence astrocytes) and surround pre- and postsynaptic nerve endings.  Astrocytes take up glutamate after this neurotransmitter is released from presynaptic terminals and also take up potassium, thus helping to maintain a constant interstitial environment.  Astrocytes participate in the coupling between blood flow and metabolism and thus regulate local vasodilation and possibly vasoconstriction in response to synaptic signaling.  They are able to extend processes that surround small blood vessels and the processes, moreover, express transporters for glucose, as well as protein channels that control water uptake (i.e., aquaporin-4).

FHM probably represent a subtype of migraine with aura inherited as an autosomal dominant disorder. Hemiplegia is thought to represent motor aura, although it continues for hours after onset. Triggering events are similar to typical forms of migraine and females are more affected than males despite its autosomal dominant pattern of inheritance. During an episode, patients experience multiple auras including somatosensory and visual as well as aphasic auras. A specific FHM-1 mutation has been knocked into genetically engineered mice. The phenotype of this mouse shows a greater susceptibility to spreading depression and enhanced glutamate release upon excitation.

Patients with FHM1, 2 and 3 have attacks of hemiplegia and headache that are accompanied by somatosensory, visual and aphasic auras.  These auras do not differ from the auras experienced by more typical forms of migraine.  Just as in typical forms, FHM appears slightly more common in females than males, despite the autosomal dominant inheritance.  Like more typical forms of migraine, FHM can often be triggered by stress, drugs, exercise, angiography and head trauma.

Migraine prophylactic drugs do not conform to a single chemistry or pharmacology. Most have been found by serendipity. Topiramate and valproate belong to the class of anti-epileptic drugs, whereas propranalol is a beta-adrenergic receptor blocker. Amitriptyline is a tricyclic reuptake inhibitor. In each case, these drugs have been shown via clinical studies to be effective in migraine prophylaxis. Methysergide, another effective prophylactic drug, has been withdrawn from the market because of untoward effects but it is still used in Europe. Importantly, these drugs have no indication for acute migraine treatment.

Recently, these drugs were found to elevate the threshold to evoke SD in experimental animals.  Chronic administration was required and the drugs were more effective over time.  At least 3 weeks were required to observe this effect.   This adaptive response may be important to understanding migraine mechanisms because such drugs suppress the number of migraine attacks when administered chronically but not acutely.

The trigeminovascular system was discovered in 1981 and describes the relation between the meningeal vessels and associated tissues, the trigeminal nerve and its central connections. Trigeminal afferents are small, unmyelinated C fibers and concentrate within the vessel adventitia. Except for midline structures, most axons project from the ipsilateral ganglia. They contain neuropeptides such as calcitonin-gene related peptide, substance P and neurokinin A. Upon excitation, peptides are released from axons and synapses peripherally and centrally, respectively. Within the periphery, they cause neurogenic inflammation, whereas centrally they promote neurotransmission. Triptan binding sites are expressed on trigeminovascular afferents and block neuropeptide release when engaged by agonist. 5-HT1B, D and F receptors have been implicated in the triptan action.

Activation of the trigeminovascular system causes headache.  The trigeminovascular system has been more completely studied in animals than man but its signature transmitter peptides have been found in human blood vessels.  Small unmyelinated axons project primarily from the first trigeminal division.  Inflammation within the meninges or activation by SD may underlie attacks, although human data are lacking in this regard.  Experimental data support the conclusion that SD is noxious and can cause pain.  These findings are in agreement with the observation that headache most often involves the side ipsilateral to the dysfunctional hemisphere.  Activation of ipsilateral thalamus or its caudal connections would cause pain and headache contralaterally and, therefore, is less likely to participate in headache pathogenesis.

CRGP (37 amino acids) and substance P (11 amino acids) have been identified within the small unmyelinated C fibers comprising the trigeminovascular system.  These peptides are stored at both peripheral and central ends of primary afferent fibers investing meningeal structures, especially blood vessels.  These peptides are vasoactive and when released into the adventitia of vessels cause vasodilation and plasma protein extravasation called neurogenic inflammation.  Leucocyte recruitment is not part of this process.  These peptides are also released centrally.  Receptor antagonists that block CGRP were recently tested and are efficacious in migraine headaches.

Trigeminovascular afferents arise within the trigeminal ganglion and express 5-HT1D and 5-HT1F receptors on their peripheral and central axons.  Occupancy of these receptors by the triptans blocks CGRP and substance P blocks calcium-dependent release. Trigeminovascular afferents do not express either GABA or VIP receptors. The triptans do not exhibit identical affinities and specificities to serotonin receptors.  Most bind with high affinity to 5-HT1B/D and 5-HT1F receptors and to 5-HT1A receptors with much lower affinity.  5-HT1A receptors do not contribute to the therapeutic effect.

In addition to effects on blockade of neuropeptide release, triptans also bind to serotonin receptors on vascular smooth muscle within cephalic blood vessels.  Occupancy of these binding sites causes vasoconstriction.  At therapeutic or even higher doses, the triptans do not decrease intracranial pressure nor do they inhibit SD.  Their site of action is thought to be limited to the trigeminal nucleus caudalis and meninges.

Migraine is a complex genetic disorder. Multiple genes, each having a small effect, along with a large effect from the environment, have been implicated.  Although several genes have been linked in some studies, the data are still not compelling and await confirmation.  More typical forms of migraine are not inherited by autosomal dominant transmission and polymorphisms in CGRP receptors have not been reported to date.

Migraine is induced by coughing? Sensitization is caused in part by a lowered threshold for activation of primary afferent fibers (primary sensitization).  It may also be caused by an exaggerated firing response of cells within the trigeminal nucleus caudalis to peripheral stimuli. According to recent experimental studies, headaches induced by coughing or raised intracranial pressure during migraine attacks are caused by primary sensitization.

Scalp and facial sensitivity. Allodynia is pain in response to non-noxious stimulus.  It typically develops during migraine attacks after many minutes to hours.  Early treatment often aborts its development.  Scalp tenderness and allodynia during an attack are attributed to secondary sensitization.   Neurons within the caudalis that receive convergent inputs from cutaneous (and subcutaneous) tissues converge on neurons receiving inputs from trigeminovascular afferents innervating the meninges.

Ergot alkaloids were originally extracted from rye fungus and used to treat hemorrhage in the postpartum period. Quite by accident they diminished hemorrhage and migraine in a young women. With advances in chemistry, particularly improved purity of extraction procedures, ergots became an important migraine treatment in the 1930s until the triptans were introduced in the early 1990s. The triptans are more specific than ergots which bind to dopamine and norepinephrine receptors as well as serotonin receptors. The ergots can elevate blood pressure and constrict peripheral blood vessels. Ergot alkaloids were used initially to constrict uterine muscle.  Originally, they were extracted from Claviceps purpurae, a fungus.  Ergots constrict arteries and sometimes veins (e.g., dihydroergotamine) and bind to multiple receptor types including serotonin, norepinephrine or dopamine receptors.

Activation of the trigeminovascular system is accompanied by central transmission of impulses into trigeminal nucleus caudalis. Second order neurons then convey impulses centrally, where pain may be experienced based on stimulation of an array of central structures. In addition, impulses reach central components of the seventh cranial nerve that drive parasympathetic activation. This activation dilates the middle meningeal artery and is a reflex autonomic response to noxious stimulation. Parasympathetic activation during cluster headache and possibly migraine result from a monosynaptic cephalic reflex arising within trigeminal nucleus caudalis and projecting to parasympathetic components that belong to the VIIth cranial nerve neurons.  With intense noxious stimulus, this reflex becomes activated by trigeminal inputs.  Sympathetic activation may also result from trigeminal inputs but this has not been well explored.

Stroke is an infrequent consequence of migraine headache.  Nevertheless it does occur in the context of migraine with aura more commonly than without aura.  Some investigators have suggested this is really a coincidence of two common disorders. However, migrainous strokes typically develop within the posterior circulation.  More recently, multiple small lesions have been found within the watershed area of the cerebellum in patients with migraine auras. Most appeared clinically silent.  High dose estrogen and progesterone preparations appear to increase the risk of stroke during a migraine attack.  The precise explanation for this remains unknown.  Dehydration and platelet disturbances have also been implicated.

Migraine is an inflammatory disorder. Non-steroidal anti-inflammatory drugs are probably the most widely used drugs to treat migraine and are clinically quite effective.  It remains unclear whether efficacy relates to analgesic properties or whether cyclooxygenase 1,2 inhibition reduces symptoms, or both.  Prednisone should only be administered with great caution and (during migraine status) and in rapidly tapering doses.  Its action inhibiting phospholipase A2 and arachidonic acid release (and downstream decrease in leukotriene and prostaglandin synthesis) has been implicated.  There are no good models for migraine headaches per se.  Nevertheless, nitroglycerin infusion infusion in humans causes delayed headaches only in migraineurs 4-6 hrs after administration. In experimental animals, the delayed appearance of Type 2 nitric oxide synthase (iNOS), interleukin-6, macrophage activation and edema appear within the meninges.  These are all markers of inflammation.

Treating Migraine

Triptans are the treatment of choice for disabling migraine.  Patients with moderate or severe headaches with moderate or severe disability (based on MIDAS) who were stratified to a triptan did better than patients given aspirin and metoclopramide.

If a patient had six disabling attacks per month for the past year, what would you do? Preventive therapy is the treatment of choice for frequent disabling headache (i.e., typically three or more attacks or prolonged attacks per month).  Acute treatment is often ineffective until prevention is started.  There is no indication for diagnostic studies.

Medication overuse and dependence: A 35-year-old woman attends a headache clinic for intractable daily headache.  She has a lifelong history of acute menstruation-related headaches which have become daily in the past five years.  She is depressed and does not sleep well.  She reports no neurological symptoms, except for persistent head and neck pain.  Several times a month she will have acute worsening of her headache associated with nausea and vomiting.  Her neurological examination is normal, except for a depressed-looking woman with terminal tremor in the upper extremities.  Her medications include:  topiramate (100 mg twice a day), amitriptyline (50 mg at bed time), oxycontin (100 mg as needed, up to three times a day), oral transmucosal fentanyl suckers (up to four times a day as needed), sumatriptan injections (three days per week) and zolmitriptan tablets (two days per week).  Magnetic resonance imaging (MRI) of her brain is normal and an MRI of her cervical spine shows modest degenerative changes.  Cerebellar tonsils are descended to approximately 3 mm below the foramen magnum.   Imaging is otherwise normal.  Her headaches are worsened while coughing and sneezing.  Her neurological examination is normal. What is this? Medication overuse headache (MOH), formerly called rebound, is a serious public health problem.  The case described here is most likely characteristic of this condition. Furthermore, the patient fits criteria for the diagnosis of chronic migraine.  Although the cerebellar tonsils are lowered by 3 mm, this is generally considered not clinically significant. The degree of opioid dependency in this individual and depression suggest hospitalization (rather than outpatient detoxification) is likely to be a more effective strategy.  Although performing a CT or MR venogram might be of some value because of the cough-related headache, it is not likely to produce useful findings as a first approach to care of this patient.  Instead, there is a compelling need to reduce medications in this individual. The literature on MOH clearly identifies a usage pattern of no more than 3 days per week as the maximum safe limits for avoiding medication overuse.  The current International Headache Society classification quantifies overusage in a “per month” manner, and usage of more than 10 days per month for most drugs is generally considered likely to lead to medication overuse. Except for Tizanidine, which is an alpha adrenergic agonist, similar to clonidine, and there are no known “rebound” effects from overuse of this medication.

Serotonin Syndrome: A 35-year-old woman with severe headaches is admitted to the hospital for treatment.  She describes several days of worsening headaches, intense anxiety, muscle cramping and palpitations.  Blood pressure is 170/110 and the patient is diaphoretic.  Prior to admission, the patient was taking 300 mg of venlafaxine, trazodone 200 mg, 50 mg of amitriptyline and 200 mg of topiramate. In addition she reports taking frovatriptan daily for five consecutive days. Treatment: The patient described has early evidence of the serotonin syndrome.  Beta blockers, serotonin blockers (cyproheptadine), benzodiazepines (clonazepam and others) and nadolol (another beta blocker) are helpful.  The patient’s serotonin syndrome was likely triggered by the combined effects of venlafaxine (an SSRI), trazodone (another SSRI), amitriptyline (an SNRI) and frovatriptan (a serotonin agonist, triptan).  The recent administration of the frovatriptan “tipped the scales.”  Valproic acid has no value. **Trazodone has been associated with priapism in male patients.

Fluoxetine: A 45-year-old woman with chronic headache who has been depressed and experiencing daily, frequent headaches is admitted to hospital.  She is taking propranolol (360 mg per day) which has provided some improvement in her headache condition but has made her even more depressed.  While in the hospital for the treatment of her intractable headache and depression, the attending physician adds 40 mg of fluoxetine to her treatment program, as well as 25 mg of amitriptyline, and places the patient on an IV DHE (dihydroergotamine) protocol.  Three days later, although somewhat improved with respect to her headaches, the patient suddenly experiences a significant cardiac event causing loss of consciousness and a serious bradyarrhythmia. Why? Fluoxetine, through the P450 system, inhibits the metabolism of propranolol, thus ultimately raising the serum level of propranolol and causing heart block.  Several case studies illustrate the risk for significant hypotension or cardiogenic syncope.

Nadolol is principally metabolized via the kidneys, making it a safer choice in patients on drugs that produce hepatocellular activity or in the presence of liver dysfunction.

Cyproheptadine: A 12-year-old boy suffered from intractable migraines and depression.  His psychiatrist placed him on fluoxetine at a dose of 60 mg a day which brought progressive improvement in the treatment of his depression but not much improvement in headache control.  A referral to a pediatric neurologist was undertaken for medication recommendations for adolescent migraine.  Within weeks of administration, the patient became progressively depressed and suicidal. We add Cyproheptadine to his treatment, which is a serotonin and histamine blocker.  Cyproheptadine may interfere with serotonin-enhancing antidepressants, including the SSRIs, and drugs with similar activity such as venlafaxine.  Cyproheptadine has been used in the management of orgasm dysfunction caused by SSRIs, as well as for the treatment of serotonin syndrome.  However, a reversal of antidepressant effects may occur when cyproheptadine is given routinely with an SSRI as a result of the serotonin antagonist effects of cyproheptadine.

Migraine treatment begins with making a diagnosis, explaining it to the patient and developing a treatment plan that considers coincidental or comorbid conditions.

Conditions that occur in migraineurs with a higher prevalence than would be expected include stroke, epilepsy, Raynaud’s syndrome and affective disorders (e.g., depression, mania, anxiety and panic disorder). Possible associations include essential tremor, mitral valve prolapse and irritable bowel syndrome. Mechanisms that account for association of these comorbid disorders with migraine are unknown.

Pharmacotherapy may be acute (abortive) or preventive (prophylactic); patients may require both approaches. Acute treatment attempts to reverse or stop the progression of a headache once it has started. Preventive therapy is designed to reduce attack frequency and severity. Acute treatment is appropriate for most attacks and should be limited to 2-3 days a week.

Depression is three times more common in patients with migraine. For treatment, we add topiramate to SSRIs. SSRIs and verapamil are often of minor benefit for migraine. Propranolol can aggravate depression. The dose of amitriptyline needed to treat depression is often not tolerated by migraineurs.

Avoid Triptans in pregnant women for they have not been proven safe for pregnant women.

Migraine aura consists of focal neurological symptoms that precede, accompany, or (rarely) follow an attack. The aura usually develops over 5-20 minutes and lasts less than 60 minutes. It can be visual, sensory or motor, and may involve language or brainstem disturbances. Headache usually follows within 60 minutes after the aura. Patients can have multiple aura types. Most patients with a sensory aura also have a visual aura.

Auras vary in complexity. Simple auras include scotomata, simple flashes (phosphenes), specks, geometric forms and shimmering in the visual field. More complicated visual auras include teichopsia or fortification spectra, (characteristic aura of migraine), metamorphopsia, micropsia, macropsia, zoom vision and mosaic vision. Paraesthesias are often cheiroaural: numbness starts in the hand, migrates up the arm and jumps to involve the face, lips and tongue. Weakness is rare, occurs in association with sensory symptoms and is unilateral. Apraxia, aphasia and agnosia, states of altered consciousness associated with déjà vu or jamais vu, and elaborate dreamy, nightmarish, trance-like or delirious states can occur. The preventive medications with the best-documented efficacy are the beta blockers, amitriptyline, divalproex and topiramate. Choice is made based on a drug’s proven efficacy, the physician’s informed belief about medications not yet evaluated in controlled trials, the drug’s associated effects, the patient’s preferences and headache profile, and the presence or absence of coexisting disorders. Coexistent diseases have important implications for treatment. In some instances, two or more conditions may be treated with a single drug. If individuals have more than one disease, certain categories of treatment may be relatively contraindicated. Some physicians would avoid use of methysergide (a vasoconstrictor) in migraine with aura because of a potential increased stroke risk.

Migraine with aura and birth control: Migraine is suggested to be a risk factor for stroke. Women suffering from migraine with aura may consider to use progesterone-only pill. Though data are conflicting, this increased risk for stroke is most clear in women suffering from migraine with aura who are 35-45 years of age, particularly for those who also smoke and use oral contraceptives.  Estrogen-containing hormonal contraception in all formulations increase stroke risk but are not absolutely contraindicated if used with caution.  Progesterone-only contraception may be considered since progesterone alone does not increase stroke risk.

Avoid Opioids unless it’s last resort: A 49-year-old woman with migraine without aura has comorbid obesity, diabetes, angina, restless leg syndrome and asthma.  She reports 1-2 attacks/month with each lasting hours. How would you treat her severe acute attacks? Opioids because Triptans are not drugs of first choice because of angina.  Aspirin is contraindicated because of asthma, corticosteroids because of diabetes and prochlorperazine because of restless leg syndrome. The choice of preventable treatment is Topiramate. Because Divalproex sodium and amitriptyline are associated with weight gain and propranolol is contraindicated because of asthma.  Topiramate is effective and associated with weight loss.  Fluoxetine has no proven efficacy.

Ergots and triptans are potent 5-HT1B/1D agonists and in some cases 5-HT1F receptor agonists. All are indicated for acute migraine treatment. Contraindications include documented or suspected ischemic heart disease, Prinzmetal’s angina, uncontrolled hypertension, basilar or hemiplegic migraine and pregnancy. There is little consensus as to how many risk factors preclude triptan use and what constitutes an appropriate evaluation.

The goals of preventive treatment are to reduce the frequency, duration or severity of attacks, improve responsiveness to acute attack treatment, improve function and reduce disability. The preventive medications with the best documented efficacy are the beta blockers, divalproex and topiramate. Choice is based on a drug’s proven efficacy, the drug’s associated effects, the physician’s informed belief about medications not yet evaluated in controlled trials, the patient’s preferences and headache profile, and the presence or absence of coexisting disorders. An underweight patient would be a candidate for one of the medications that commonly produce weight gain such as a tricyclic antidepressant (TCA). In contrast, one would try to avoid these drugs and consider topiramate when the patient is overweight. Older patients with cardiac disease or patients with significant hypotension may not be able to use TCAs, calcium channel or β-blockers but could use divalproex or topiramate.

Acute treatment can be specific (ergots and triptans), or nonspecific (analgesics and opioids). A non-oral route of administration and an antiemetic should be considered when severe nausea or vomiting is present. Early intervention prevents escalation and may increase efficacy. Triptans can prevent the development of cutaneous allodynia and cutaneous allodynia predicts triptans’ effectiveness. Before deciding that a drug is ineffective, at least two attacks should be treated. It may be necessary to add an adjuvant or change the dose, formulation or route of administration. NSAIDs are synergistic with triptans.

Central sensitization: A 20-year-old man with migraine only partially responds to his triptan taken when the pain is moderate. Why? Peripheral sensitization leads to central sensitization but does not itself produce refractoriness to triptans. Glial activation is involved in central sensitization and Allodynia is a sign of central sensitization. Triptans and NSAIDs are synergistic.  Early intervention increases triptan effectiveness.

Preventive medications reduce attack frequency, duration or severity. Indications for preventive treatment include migraine that significantly interferes with the patient’s daily routine despite acute treatment; failure of, contraindication to or troublesome associated effects from acute medications; acute medication overuse; very frequent headaches (>2/week, i.e., risk of medication overuse); patient preference; special circumstances, e.g., hemiplegic migraine or attacks with a risk of permanent neurological injury.

Preventive medication groups include beta-adrenergic blockers, antidepressants, calcium channel antagonists, serotonin antagonists, anticonvulsants and NSAIDs. Choice is based on efficacy, associated effects, and coexistent and comorbid conditions. Preventive medication is started at a low dose and increased slowly until therapeutic effects develop or the ceiling dose is reached. A full therapeutic trial may take 2-6 months. Acute headache medications should not be overused. If headaches are well controlled, medication can be tapered and discontinued. Dose reduction may provide a better risk-to-benefit ratio. Women of childbearing potential should be on adequate contraception.

How to judge a preventive medication’s effectiveness: A 39-year-old woman with migraine without aura has 6 disabling attacks per month.  She has been started on propranolol at 60 mg/day. Her pulse is slowed. What can increase its effectiveness if she does not find it of benefit after two weeks? In general, a medication with documented efficacy for migraine prevention should be continued (if there are no contraindications to continued treatment) for 6-8 weeks before deciding it is not effective in a given patient.  Two weeks is too early to judge its effectiveness.

Increase the dose: What can increase its effectiveness if she does not find it of benefit after 6-8 weeks? Her pulse is unchanged: The duration of treatment is adequate. The dose response to propranolol is idiosyncratic.  With no change in pulse rate, she is most likely underdosed and, therefore, might benefit from increased propranolol.

Alternative treatments: The propranolol did not work and she wants an alternative treatment? Biofeedback and relaxation therapy are proven effective. Acupuncture’s efficacy is still on the works.

Natural products: Coenzyme Q10 has been shown to be consistently effective in controlled clinical trials.

Cluster Headaches

Primary short-lasting headaches are divided into those with prominent cranial autonomic symptoms and those where autonomic symptoms are minimal or absent. Trigeminal autonomic cephalalgias (TACs) comprise a group of headache syndromes usually marked by cyclical episodes of severe head pain with cranial autonomic activation. These headaches include cluster headache, paroxysmal hemicrania, SUNCT syndrome (i.e., short-lasting unilateral neuralgiform headache with conjunctival injection and tearing) and hemicrania continua. Other short-lasting headaches are idiopathic stabbing headache, benign cough headache and hypnic headache.

Cluster headache is the most common of the TACs; while rare relative to other primary headaches, its prevalence is similar to multiple sclerosis. Its importance as a primary headache derives from cluster headache’s extraordinary morbidity. The pain is devastating and the syndrome is both unique and gratifying to treat successfully; as a consequence, physicians with an interest in head pain should be acquainted with the condition.

The image of the tortured cluster headache sufferer rocking or pacing in the dark, with tears streaming from one eye and a face contorted in exquisite pain, is distinctive and compelling in medicine. The individual attack is called a cluster headache or cluster attack. Attacks occur in series that last for weeks or months (called cluster periods), with the attack frequency ranging from one every other day to eight a day. The cluster periods are separated by remissions that usually last months or years. On average, a cluster period lasts 6 to 12 weeks, while a remission lasts 12 months. Considerable variations, both between patients and in individuals, are characteristic. About 10% of patients have chronic symptoms with no remission periods. Cluster headaches occur more commonly in males.

ICHD-2 diagnostic criteria for cluster require at least 5 attacks of severe, unilateral, orbital, suborbital and/or temporal pain that last 15 to180 minutes if untreated and are associated with at least one of the following — conjunctival injection, lacrimation, nasal congestion, rhinorrhea, forehead and facial sweating, miosis, ptosis or eyelid edema during the headache. Furthermore, the headache can occur in two forms: episodic, which occurs in periods lasting 7 days to 1 year separated by pain-free periods lasting one month; and chronic where attacks occur for more than one year without remission or with remissions lasting less than one month.

Cluster headache must be differentiated from the other TACs, particularly paroxysmal hemicrania, which resembles cluster headache pain but is seen more commonly in females, and consists of attacks that are relatively shorter and more frequent. Some recommend a trial of indomethacin for patients who have episodic cluster headache and do not respond readily to treatment. Hemicrania continua, a unilateral, moderate and fluctuating severity, continuous headache (responsive to indomethacin) can be mistaken for cluster headache if the history focuses on short-lived unilateral exacerbations of pain and misses the chronic low level of pain between exacerbations.

Verapamil: A 30-year-old man presents with a 2-year history of extremely severe daily headaches. They are left-sided (around the eye) and associated with ipsilateral lacrimation and nasal congestion. If they occur 3 times per day and last 60 minutes the most likely diagnosis is chronic cluster headaches. The frequency (3/day) and duration (60 minutes) define cluster headache with this location and associated symptoms.  Duration over two years makes it a chronic form. Treatment of choice is verapamil. Because propranolol, indomethacin, amitriptyline and lamotrigine are ineffective for cluster headache.

The frequency (10/day) and duration (20 minutes) define paroxysmal hemicrania.  This is a higher frequency and shorter duration than cluster headache. Paroxysmal hemicrania is one of the indomethacin-responsive headaches.

The frequency (constant) and duration (constant) define hemicrania continua. Hemicrania continua is another indomethacin responsive headaches.

TAC: A 30-year-old gentleman experiences the onset of headaches three months earlier.  Attacks last 15-45 minutes, occur several times a day and begin in the right eye.  Conjunctival injection, tearing and nasal drainage accompany the attacks.  During the attacks he occasionally bangs his head and frequently paces.  The attacks may occur up to 6-8 times a day.  The patient failed to respond to verapamil, lithium, methysergide, valproic acid, topiramate and baclofen.  Only as needed treatment with oxygen and injection of sumatriptan produce a favorable response.  Steroids bring relief but only while on high dose.  Neurological examination is normal.  Brain imaging is normal.

Physical and personality characteristic in cluster headaches: Among the non-headache features of cluster headache in majority of patients are hazel-colored or blue eyes. However, exceptions are common, making this physical characteristic of little diagnostic specificity.  Another non-headache feature of cluster headache patients is a tendency for heavy smoking, noted in 85% of cases.  The patients also tend to show heavy alcohol intake.

Indomethacin is therapeutically, if not diagnostically, relevant to the treatment of other trigeminal autonomic neuralgia (TACs) such as chronic paroxysmal hemicrania but has not been systematically evaluated for cluster headache.

Deep brain stimulation: If a case describes a cluster headache patient who has essentially failed to respond to standard treatments, current research clearly demonstrates that the hypothalamus is directly involved in the pathogenesis of the disorder and that deep brain stimulation has been initially effective in treating intractable cases. The hypothalamus is intimately involved in the pathophysiology of cluster headache and a growing number of cases have been successfully treated by deep brain stimulation of the posterior hypothalamus.

Diffuse meningeal enhancement: A 75-year-old woman reports having three months of intractable headache.  Initially the woman experienced a severe headache one morning upon arising from bed.  She found that lying down produced significant improvement but upon standing she would experience progressive worsening of her headache.  Currently, however, the positional features are absent, in contrast to her symptoms initially.  She now experiences persistent daily headache and neck pain without positional elements.  Her neurological examination is normal, except for limitation of neck movement.  MRI of the neck demonstrates diffuse degenerative arthritis.  An MRI without contrast of the head shows age-related changes only. An MRI with contrast would likely show diffuse meningeal enhancement. This case is that of a woman with spontaneous intracranial hypotension.  A characteristic feature is diffuse meningeal enhancement on MRI imaging. Diffuse meningeal enhancement is a compensatory reaction thought to result from the body’s attempt to enhance blood flow to increase cerebral pressure.  The pachymeninges appear diffusely enhanced on imaging. Perform a spinal tab and you will see that an opening pressure less than 50 mm water is characteristic of the case described.  Although segmental meningeal enhancement may be seen in a variety of conditions, diffuse meningeal enhancement is quite characteristic of low pressure syndrome, and a pressure below 50 mm of water is characteristic of this condition. In the presence of low CSF pressure, IV lactated caffeine is known to raise pressure and temporarily relieve symptoms.  The mechanism by which pressure is increased remains speculative but it is thought to involve increased blood flow.  Topiramate has carbonic anhydrase inhibitor activity and thus can lower intracranial pressure. In low pressure syndromes, placing a patient in the Trendelenburg position can sometimes be temporarily helpful, if not support the diagnosis. Epidural blood patch is often therapeutic for this condition.  The “blood patch” is not truly a patch but a tamponade, which by instilling fluid into the epidural space, raises pressure in the canal and upward into the intracranial cavity.  This can result in amelioration of the condition.  The “blood patch” can be administered well above the site of the leak and diffuses up and down for several segments.

Thank you for reading.

Michael

 

 

Neurotransmitters: Crazy in Love

It all starts when your frontal lobe tells you to have sex with a person and Cupid’s arrows find their marks. There it is but where is the magic? The concept of self is an ongoing complex pattern of firing neurons. Every perception of our thoughts is all neuroscience, magic is within our brain.

What is the most powerful aphrodisiac that we know of? Think about it… Found it? Okay. Let me tell you, it is uncertainty. There is nothing else that drives your brain as wild as doubt does. Dopamine’s release is too high when in love.  What does dopamine promote? “Explore! Learn! Ask! Wonder! You are rewarded!”

If we’re talking about passionate love, your serotonin levels are too low. Sorry, I really didn’t mean to be the one breaking the bad news. Serotonin gives us a sense of security, stability, well-being. Sweet. In converse, we become possessive, insecure, obsessive, aggressive when in love. Which doesn’t necessarily make us feel positive but now, let’s think about evolution.

How do you choose your mate? Their looks. It’s a natural selection. Love is known as devotion in animals, it’s nothing more complex than a primal instinct ensuring mating. Instincts always come before intellectual thoughts however learning to think clearly and care about each other calmly ensure the survival of intellectual species even if they don’t have survival advantage. We have vaccination now. We have “healthy lifestyle” tips. We’ve come so far, we’re not just advanced animals anymore and every person deserves to have a long, healthy life. Even the weak ones do mate, breed and nurture their species. It’s no longer the destiny of intelligence to primarily ruled by blindly devoted emotions, either. However still, in 2011, we primarily desire the lucky ones. That’s why we fall in love once. Or twice, if you’re lucky enough. We want to mate with those “hot” people because we want their babies. Looking good means to have more offspring for some odd reason. Being a good person…is not even listed. For animals, to say at least.

Thus, let’s just say your partner is at risk, is it advantageous for you to be comfortable or aggressive and possessive? You know the answer. You can always need to be a superman or a super girl to rescue your mate. Therefore, your serotonin levels are low for your advantage. High serotonin levels, which can be found in comfortable people, kill the libido, it can’t be a good thing. Right?

Aggression can cause emotional blindness and sufferings, this is when you need your evolved intelligence. Cortisol is too high, really, how stressed are you when in love? “Where, why, how, when, what?” Questions only lead to even more questions and no answer can give you a sense of calm. You know when you sit there, think, think, think and explode? Passionate love and too much stress. It’s a package deal.

However, no one can have the best of both worlds. If you want love, you have to sacrifice just too much. Your brain says it all. You don’t want to get hurt? Erm, I mean, you want high serotonin levels? Then, you can’t love. You don’t need to feel the high pressure of obsession? Dependance scares you? Good, then, abstain from love.

Most people miss the chance of mating with their true loves because these feelings naturally scare them off. They want a mature relationship,  but relationships mature with age — so is wine. They don’t want to risk anything but I think risking nothing is more likely to risk everything. Mating with “unlucky species”? What is the big deal? Well, you risk your kids to feel a sense of comfort. If you mate with the right person who gave you the heaven and the hell at the same time, you may have a genius kid? Or a beauty queen? It’s natural selection! Remember? Wrong mating always leads to some preventable consequences and ultimate disappointment. Nature is apathetic, and may not give you another chance. Choose wisely.

Crying through the nights, who would enjoy that? Over analyzing everything? Worrying? Obsessive thinking? Fighting over bullshit? How draining it would be to feel unbelievably desirous all the time? It’s not fun to have an unstable relationship, is it? But if you still think so, you miss the whole point, the pleasure passionate love introduces can be compared with no other pleasure in this world. Dopamine? Check. The ventral tegmental floods the caudate with dopamine. God. This is the true magic because seeing someone in half doesn’t fascinate you as much. You know I am right.

Let’s skip to cognitive functions now. When you’re not in love, you over criticize your partners because you don’t see them better than own, in order words — you think they are killing you smalls. No matter what they do, they can’t please you. What kind of love do you expect to experience in the absence of admiration? “You ass, you forgot your socks on the bedroom floor? Again?” How is this a big deal? You just don’t find that person worth admiring or respecting because you’re not in love. Simple. The main problem in relationships derives from repugnance. Again, you risk too much for comfort if you are scared to be in love.

Another aspect of love is the understanding. Nowadays, everyone I know seems to be complaining about how their partner is not understanding. I tell them that it’s because they’re not in love with them. Sorry. “I just wanted him to know it before I tell him.” Well, he never will. It’s called social cognition and it’s heightened when in love, you understand your partners’ intentions, you just do because you’re focused.  Significant activation on the hippocampus, man.

You know the feeling when you eat chocolate? It just tickles your reward system, including septum. Bad news, love can be excessively addictive, more addictive than chocolate but you get addicted to the person. Love is the strongest drug, but its addiction…meh. Nothing feels better than a broken heart, huh? It can kill, in my brutally honest opinion. Get the person back, if there is no way for you to get them back, get professional help, you can only suppress those unchallengeable seductions for so long before you become too numb.

 
I already mentioned how cortisol levels are heightened when in love, which means you are stressed however it was the bad news, in converse, your sensitivity to pain is incredibly low. It’s a miracle, if you ask me. You don’t feel the pain, you can have the nastiest headache known to mankind but just thinking about your sweetheart can still melt you. Having a bad day? You have no bad days when in love. You talk to your partner and they brighten your worst day. Your partner orchestrates your day, in clearer words. Also, cortisol increases the alertness which increases the focus. Which increases the success.

Love changes everything.

Well, not really, for example, oxytocin does — rather. The heightened levels of oxytocin makes you trust unconditionally and triggers attachment as well. Yes, you can mate for life like the penguins. Also, high oxytocin levels means to have no fear. Being dependant, obsessive, aggressive, stressed, impatient and brave? Oh boy.  It’s a good timing (and a bad timing) to take big steps in regard to your career when in love because you become brave, you are willing to stand up for your own rights and take risks. You discover your voice when you need it, love gives you confidence. However, you may become too  courageous. Moderation is safer. Practice self-control. In a pessimistic perspective, you make your biggest mistakes when in love but optimistically speaking, nevertheless, it’s worth the feeling.

Our last guest is my personal favorite. Vasopressin, vasopressin, vasopressin. This guy is the shit. When you think about how it’s just some nine amino acid peptide secreted from the posterior pituitary, it sure doesn’t look as cool but when it puts on a show, you are blown away. As you can tell from the way I introduce it, yes, it’s released during and after sex.

I don’t generally believe in monogamy because I don’t think it could be a moral “ought”, since the reasons it doesn’t happen aren’t in anyone’s control, but there is this study on the link between vasopressin and attachment. Do you know prairie voles? They are really cute and they release oxytocin and vasopressin during sex just like we do and they mate for life. If you block the release of these neurotransmitters, they will be promiscuous and sleep with others mainly because they are not satisfied. Sounds familiar? I know. Creepy. Then, on the other hand, there are montane voles, they never mate for life because they don’t release these chemicals during sex. You can artificially stimulate them on the occasion of sex but they still won’t mate for life. They enjoy being promiscuous? Everyone does. Not really, they just don’t have receptors in their brains for these hormones. Other than this tiny genetic difference, these two guys are pretty much genetically the same. That’s why they even tried genetic manipulation which did the trick for montane voles whereas it removed the ability to form a monogamous bond from prairie voles. Therefore, monogamy is just a gene. Bonding is just a chemical reaction. A chemical basis for at least the stuff we have called romantic infatuation? Bad news panda. We want to believe that animal desires can be sublimated by higher emotions, such as rational belief formations or romantic love — it is not true. Higher thought processes are not responsible for the association between sex and a particular partner. One sexual act is enough to create a permanent bond between prairie voles whereas this doesn’t necessarily happen with humans. Why might that be? Given our appreciation for long-term genuine love and its being a goal that favors selection with evolutionary advantage, is this study a scientific fact that it should?

Well, Hume said there is a significant difference between what it is and what it ought to be. Thus I am leaving your rational appetite be for the time being.

Don’t engage in sexual intercourse with those you wouldn’t want to fall in love with. Testosterone increases sexual desire by stimulating dopamine in the brain, dopamine makes you addicted to the pleasure and orgasms elevate the attachment of hormones. You can indeed, immediately fall in love and want to mate for life after one sexual act. God, I can only hope it doesn’t enhance morons’ chances of “transmitting” their genes.

Ask yourself, who would love us in spite of ourselves if it wasn’t for this magical reaction in the brain? No one.

Casual: Philosophical Morality and Faith-based Morality

The thing about religious people is — that they claim that atheism leads to amorality, because objective morality derives from belief in a supernatural power and your philosophical morality has no objective basis, then ultimately, your morality has to be subjective, which in and of itself turns out  to be a fundamentally false dichotomy.

First of all, if I have to address a few premises; a creationist is usually found equating atheism with belief in evolution, even though this is not valid, I will nevertheless continue for the moment to give them that atheists tend to accept evolution mainly because there is no logical reason to dismiss a scientific fact — If I were you, I’d be cautious and call it a “consensus” rather than a fact in order to avoid giving any creationist the chance to debate because it’s not a fact in the scientific sense of the term. -. The trouble is when you equate evolution with being unguided, searching for life’s origins, and doing everything to pass on your genes. Darwin’s grand idea of evolution by natural selection is relatively simple but it is not only the literal creationists who have doubts about evolution and natural selection because natural selection is commonly misunderstood.

Environment can’t support unlimited population growth, thus not all individuals can reproduce to their full potential. For example, if you are a green bug and are tend to be eaten by birds because you are green, you will survive to produce less often than your red bug friends and surviving red bugs will presumably have red baby bugs on a genetic basis. This adventageous red coloration trait allows the bug to have more offspring, and red consequently becomes more common in population, this progress continues and all bugs will eventually be red in the population. It’s as simple as that; you need heredity, variation, differential reproduction, survival advantage then you will have evolution by natural selection as an outcome.

However, evolution is not all about killing. Humans in particular are known to be cooperating, even self-sacrificing social species who derive this survival advantage from guarding over their family to the point of self-sacrifice. Evolutionary forces do not lead to killing in an inexorable manner.

We have evolved many moral senses; for example, reciprocity. Even though, reciprocity may seem to be a cold calculation (not as cold as doing good to go to Heaven), not every individual is making a cold calculation, either we do good to others so they will do good to us or we actually feel that doing good to others is the right thing to do, we evolved a sense of justice; we know that those who do bad deserve to be punished. We also genuinely love our family and extend this love to our social division of people — whatever we perceive that to be. There is also a negative aspect — that generally progresses to be positive — of these evolved senses in which we are inclined to dehumanize those we categorize out of our tribe which leads to a set of moral emotions, social connections, taboos but definitely not killing, we don’t murder those we categorize out of our tribe.

Yet another core point claimed by creationists is morality should be subjective unless it’s supported by a supernatural power. Where they get trouble in equating morality with rule-following is that if it’s subjective, it’s your opinion – it’s just YOUR opinion that this is subjective. But don’t we all “instinctively” know that murder is wrong then why do we need a moral fiber woven into the fabric of universe by God to know that murder is wrong? Perhaps we don’t need such a supernatural cause of our instinct, perhaps we just evolved that moral sense because it’s a “survival advantage”.

Evolution is not the only source of morality but they are also known to ignore the primary source of non-supernatural morality — philosophy. If it’s not descended from heaven, then it’s just an opinion. Haven’t philosophers for several thousand years worked out a system of morals that is more than opinion? Before anyone criticizes non-religious morality, they need to read a good book on morals.

It appears to our evolved sense of justice that all people should be considered to have equal rights, which can be reasoned to be the basic principle of equality and without this princible there is no way to devolop a moral system, the implications of a moral system without equality have been thought by philosophers over the years and this has been the only conclusion that works. Yes, I agree that even still this moral system is NOT metaphysical certitude but it’s absurd to define anything less than hypothetical certitude either in terms of subjectivity,  or as the absence of morality. Our moral system is far more than just an opinion, it is functional, logical, practical and fair. As we face new challenges, we will have to adapt our moral code to those challenges. No moral system is absolute, or perfect, but it is the best we have and it works.

One last thing is that how come we would “know” that a moral code derived from God is objective when it’s not even estabilished that there IS a supernatural power? Even if there is a supernatural power, we do not have access to it. You have no valid argument to claim that our innate moral sense is an evidence of a supernatural power, since evolution is workable explanation for such moral senses. Further, where is the evidence for any specific form of any alleged supernatural power? How is there an objective way to distungish among the hundreds of conceptions? Who is your “favorite” supernatural power in the universe? Who do you listen to, Moses, Jesus, Mohammed, Buddha when the moral lessons are ambigious? I don’t know if you read Torah: God tells Moses and his followers to not kill but then commands them to murder every woman, child and man in an enemy city. So, God’s commands conveyed through a priest who dictated the will of God and interpreted the morality of universe mean that murder is ok? Therefore, there is no evidence of an objective morality that we have any privileged access to. We are left to figure out what morality might be for ourselves.

In the end, the authority of faith-based morality is ambiguous, questionable and subjective, while philosophical morality follows a transparent and logical pattern and is, ironically, more objective because ethics cannot be based solely on theoretical principles.

So… Finally some Neurosurgery: Glioma

I thought it was finally time for me to write about brain tumors, since they are what I resect for a living. Today, we will be discussing about Gliomas. Bear with me, this may not be “glioma for dummies” but I will do my best in order to dumb this one down. :)

Okay.

Primary malignant gliomas can be classified into three major groups that we will discuss today. The first glioblastoma has been designated grade four by the World Health Organization. The second category anaplastic gliomas can be subdivided into anaplastic astrocytoma and anaplastic oligodendroglioma and have been designated grade three tumors. The last category low grade gliomas, WHO grade two gliomas, include low grade astrocytoma and low grade oligodendroglioma.

Approximately two hundred ten thousand people in the United States will be diagnosed with a primary or metastatic brain tumor. Sixty thousand of those cases will be primary tumors and one hundred fifty thousand of those will be metastatic tumors, that is tumors that originate elsewhere. Currently over six hundred thousand people in the United States are living with a primary brain tumor, including all benign and malignant brain tumors. Approximately twenty thousand new cases of malignant brain tumors are diagnosed annually in the United States. Importantly, brain tumors do not discriminate against age, race, sex, or socioeconomic status. Anyone is a potential candidate. Malignant gliomas are the second cause of cancer related deaths in patients under thirty-five years of age.

Treatment planning for the management of malignant gliomas involves a variety of disciplines. In neurosurgery, the questions are surgical and imaging techniques to maximize the resection while minimizing the risk of neurological disability. In radiation oncology, the important questions are what to radiate, when to radiate, how much brain to radiate and what type of radiation to use. In medical neuro-oncology, we have an abundance of systemic treatments, which include chemotherapy, novel immunotherapies and new targeted agents, which are at various stages of clinical testing. This involves a team approach in order to carryout clinical trials, which involve multimodality therapy and manage patients over the entire course of their disease, as well as provide assistance to families and provide necessary support.

Observationally, there have been two groups of patients who develop glioblastoma. There are younger patients, who initially present with a lower grade tumor who, over time, progressed to glioblastoma. There is a separate group of older patients who present with glioblastoma. Molecular studies have shown that those who develop glioblastomas over time have a p53 dependant mechanism.

Those who develop rapid onset adult glioblastomas have a different path through p10 and eventually progressing to those tumors with a significant number showing epidermal growth factor over amplification. These factors have prognostic and therapeutic implications. Surgery for malignant gliomas has evolved quite significantly over the last several years. It has now become clear that extended resection for both low-grade and malignant gliomas is an important clinical variable. However, major morbidity still exists for neurosurgical oncologic procedures and approaches thirty-percent. The field has relied quite heavily on developments in advanced imaging, (which we will discuss today). Contemporary surgery involves the use of conventional and advanced MRI, as well as techniques for functional MRI: awake (craniotomy), and speech and motor mapping in the operating room. The surgical resection of malignant gliomas involves the use of surgical navigation, again utilizing MRI technologies.

The surgical extent and outcomes is a well-known clinical observation. In 1995, total resection of malignant gliomas improved survival. These data have been supported by more recent studies in both low-grade and high-grade gliomas, indicating that extent of resection is an important clinical variable for the outcome of patients with both low and high-grade gliomas.

Glioblastoma

I will now go to the first case involving a forty-four-year-old man with a glioblastoma of the left temporal lobe. Specifically this mass involves the insular cortex beneath the temporal lobe in close proximity to language and speech function. The question is how would one go about treating a patient with this mass in this particular eloquent location?

Glioblastoma

 

The case involves a ring-enhancing mass with regular margins, at pretty much the junction of the left insular and the left temporal lobe. This case is nice because I would like to use it to demonstrate how we have an advanced imaging protocol that includes several MRI sequences; some of which are used to help plan and perform the surgical resection. I will be discussing some of these in some of the other cases. But, in this case, I would like to show how some of the sequences can help us differentiate between GBM’s or glioblastomas and other tumor-like processes, which at a first glance may look like a glioblastoma but actually are not, and that’s very important because these are sometimes treated very differently.

I want to show the typical features of a glioblastoma. You can see an irregular ring-enhancing lesion here in the left parietal occipital lobe on the top. The top two images show a perfusion-weighted scan, which shows high microvascularity within the tumor, and this is very typical of glioblastomas. And then the figure to the lower right shows an MR spectrum. This shows some of the concentrations of metabolites in the tumor, and there is a very characteristic elevation of choline and depression of NAA, that is N-acetylaspartate, as well as a marked elevation in lipid and lactate. This spectrum is, well, it is not diagnostic; it is very characteristic of glioblastoma.

Typical features of a GBM

Mimics

Abscess mimicing GBM

Here is a ring-enhancing lesion. This one is in the left frontal lobe, which at first glance might appear to be a glioblastoma. The other sequences, however, show differently. The image in the middle is from a defusion-weighted sequence, which shows very high signal within the center of the lesion. This is a feature, which often times is seen in bacterial abscesses. The spectrum to the right is really the clincher because the spectra shows several abnormal metabolites, which are generally not seen in glioblastomas. These include a succinate peak. You can see that at 2.4 PPM and also an acetate peak at around 1.9. These are abnormal metabolites, which are sometimes seen in anaerobic abscesses, which indeed this turned out to be.

Tumor factor demyelination mimicing GBM

Here is another rim-enhancing lesion. This one in the left hemisphere. But, at closer inspection, you can see that the irregular rim-enhancement is actually only a partial ring. This is a feature that is commonly seen in tumor factor demyelination, not an actual neoplasm but rather a florid inflammatory reaction, which can sometimes mimic a tumor. This impression is corroborated by the advance imaging where the perfusion with the image you will see on the right shows only a very mild elevation of cerebral blood volume unlike the glioblastoma-which I showed earlier, which showed a marked increase. So these features argued towards a non-glioma process, and this indeed was tumor factor demyelination and was treated without surgery.

Subacute infarction mimicing GBM

The last case as I like to describe as mimicing malignant gliomas is a case of ring-enhancing lesion in the right occipital lobe, as you can see on the images above. But there were some features about this one, which similarly were unusual for a glioblastoma. One, the amount of signal abnormality around it on our flair sequence was relatively small for a glioma. Second, the perfusion-weighted imaging, as you can see on the lower right, similarly did not show a marked increase in perfusion as would be expected in a glioblastoma. Finally, just based on the location and the shape of the ring-enhancement, it really does conform to a vascular territory similarly as would be seen in arterial infarction. Therefore, this case was indeed simply a subacute infarct and not a malignant glioma.

Advanced Imaging as a part of preoperative planning

Getting back to the original case, as we were discussing with the ring-enhancing lesion in the left insular and temporal lobe, for the advanced imaging on this case, I actually performed two different types of perfusion. Arterial spin labeling is a technique, partly developed by faculty at our institution, where I can get perfusion information, that is to say measures of vascularity at the capillary level. I can get these measures without an injection of intravenous contrast. The DSC method on the lower left is the more standard way to get perfusion imaging data, and, as you can see, they are very similar. In this lesion, they both show markedly elevated perfusion in this lesion, again supporting the diagnosis of a high-grade malignant glioma. The spectroscopy as I show on the right also shows a similar brain tumor spectrum with elevation of choline and depression of N-acetylaspartate or NAA. In fact this inversion of the normal ratio is quite commonly seen in malignant gliomas.

Now I will be discussing in this case the importance of us localizing language function in the left hemisphere given the location of the lesion. I can perform so-called BOLD imaging that can localize important areas of brain function in language or in motor activity, and in this case I was able to localize important areas of receptive language very close to the tumor.

 

fMRI for preoperative analysis of receptive language

Functional MRI imaging has become a very important surgical adjunct. The two pictures (above and below) show both the depiction of receptive language and the production of language. In the top picture, we see a red area which indicates increased blood flow in an area felt to be important during this process for the understanding and comprehension of speech, and as you can see it is on the periphery of the tumor, quite close, but on the posterior border of the mass. The lower picture shows a word generation task, which in this particular case, as expected, shows that the production of languages is at the anterior boarder of the mass. So in summary, we have a test, which shows us before surgery where we are likely to find language function in the operating room in order to avoid that function and preserve speech, production, and understanding.

fMRI

I am able to accomplish a complete resection of the tumor by utilizing this information before surgery and by complementing this with awake speech mapping in the operating room. That is a technique during which we directly stimulate the cortex of the brain in the areas that are suggested to be important for language, by the functional MRI, in order to confirm that in the operating room and with surgical navigation be able to remove the tumor and avoid those areas. A complete resection of the tumor is, therefore, achieved utilizing a combination of advanced imaging techniques before the operating room and speech mapping in the operating room.

 

Diffuse malignant glioma, WHO III gliomatosis limits extend of resection

This fifty-five-year-old male presented with a single seizure and was found to have a diffuse tumor. In this case, the WHO grade three tumor referred to as gliomatosis is a more diffused process of malignant glioma.

 

Intraoperative motor mapping

This shows the important use of intraoperative motor mapping to perform a limited but important resection of this tumor. The location of this tumor was within the precentral gyrus of the brain, which is the critical primary area for motor function. As you can see in the top panel, small strips have been placed on the brain identifying critical areas of primary motor function in the left-upper and lower extremity. The lower panel shows that limited resection of these regions was achieved with minimal neurological deficit utilizing intraoperative motor mapping.

After surgical resection, radiation therapy should start within four to six weeks. There are a number of questions that we will need to answer. The first is what volume of the brain should receive radiation, and the second is what dose of radiation should be delivered. Studies doing biopsies beyond the area of the tumor have shown extension of tumor cells two to two and a half centimeters beyond the abnormal area on the MRI. In addition, studies looking at patients who received whole bran radiation therapy showed that seventy-eight percent recurred within the two-centimeter margin of the tumor and fifty six percent recurred within a one-centimeter margin of the tumor. Therefore, this is not necessary to radiate the entire brain but to use current imaging modalities to set-up a field limited to the area of the tumor and the immediate surrounding areas.

Altered fractionation of radiation therapy has been investigated to evaluate its ability to improve outcome in the treatment of glioblastoma. Studies have looked at twice a day fractionation. Are they using small fractions of one point two twice a day or larger fractions of one point six Gy twice a day? Additional studies have been carried out to higher doses from the standard dose of sixty Gy to up to seventy-two Gy. Unfortunately, none of these studies have shown significant benefit in altering the outcome in glioblastoma.

Other modalities of radiation therapy have been investigated to evaluate their use in controlling glioblastoma. Stereotactic radiosurgery involves the use of multiple focused beams of radiation to a small area within the tumor, which has the highest likelihood of recurrence. Although initial phase two studies showed some improvement, when tested in a randomized study, this did not show any significant advantage. Brachytherapy or implantation of radioactive sources directly into the tumor has also been investigated as a boost. While there was some improvement in overall outcome, there was a very significant increase in the radiation necrosis, which was due to swelling of the tumor requiring further surgery.

For the treatment volumes and doses for glioblastoma, the initial volume consists of the clinical target volume which is the surgical cavity plus the residual enhancement or edema noted on the MRI plus a one point five to two centimeter expansion. A three to five millimeter planning target volume is then added to account for uncertainty or motion during the treatment. This volume is treated at two hundred centigrade per fraction to a total of forty-six hundred centigrade. The areas then decrease in size to include the surgical cavity plus a one point five to two centimeter expansion with the additional planning target volume expansion of three to five millimeters. The dose to this volume is two hundred centigrade per day to a total of fourteen hundred centigrade. Thus, the total dose to be delivered for this tumor is six thousand centigrade in thirty fractions over six weeks.

Anaplastic oligodendroglioma

I will now introduce the topic of anaplastic oligodendrogliomas. This is a particularly interesting subset of malignant gliomas that was found during studies that began in the 1990’s to show increased sensitivity to both radiation and chemotherapy. These tumors are designated grade three, and, therefore, are malignant gliomas. Cytogenetic analysis, however, reveal that chromosomal losses on number 1p and 19q represent a more sensitive tumor type. Losses at chromosomes 1p and 19q are more predictive of clinical behavior in tumor sensitivity than histologic features of the tumor that maybe appreciated by a neuropathologist.

These tumors can be stratified into the presence or absence of 1p loss. And further, they can be stratified into more specific groups based on additional genetic changes. The major point is that loss of genetic material on chromosome 1p predicts a more favorable survival. Whereas patients who have tumors within intact 1p locus have a poor survival. We are additionally learning that other genetic changes in association with 1p loss or gain have prognostic and treatment implications.

Non-enhancing lesion in right superior frontal gyrus

This illustrates the patient with an anaplastic oligodendroglioma. This is a non-enhancing lesion in the right superior frontal gyrus in a thirty-year-old male who presented with seizures. This tumor was shown to be an anaplastic oligodendroglioma WHO grade three and we will now discuss the management of this case.

Fiber-tracking

In order to illustrate an important additional adjunct of imaging technique called diffusion tensor imaging, check out the pictures above. As I stated previously, this patient’s tumor was located in the superior frontal gyrus in close proximity to primary motor and supplementary motor cortex. As is shown, you see the motor fibers mapped out clearly in their proximity to the tumor mass, it nicely demonstrates how the diffusion tensor imaging technique can help us visualize the important white matter pathways around a tumor. In this case the tumor is in the superior frontal gyrus very close to the motor fibrers. So in this technique, I was able to visualize and know exactly how the tumor is displacing the motor fibers posteriorly. The image also shows for comparison the normal course of the fibers on the other side labeled left.

The diffusion tensor imaging sequence allows a complete removal to be achieved with no motor deficit. And following surgery, many questions arise regarding the proper course of treatment for anaplastic gliomas.

The real question for anaplastic gliomas is is there a standard of care. We have covered that patients with anaplastic oligodendrogliomas often have longer survivals than those patients with anaplastic astrocytomas but in some cases, these tumors can appear as aggressive as a glioblastoma. Should these patients receive Gliadel wafers? Should they have radiation? Should they have radiation chemotherapy and chemotherapy after radiation? Perhaps they should not have any radiation. Should they only have chemotherapy? These are really important questions.

I want to remind, once again, of the data about the 1p genetic analysis, so that you can keep it in mind as we move forward. Patients with anaplastic oligodendrogliomas who have loss of 1p chromosome have much longer survivals than those patients who have intact 1p chromosomes.

What this data makes one think about is whether we need to reclassify our anaplastic tumors before we decide on how to treat patients. This proposes a new classification scheme: where we take all anaplastic tumors, whether they are anaplastic oligodendrogliomas or anaplastic astrocytomas, and separate them out into those that have 1p loss and those that do not. And then, using this classification, we can move forward and do studies on these individual groups of patients to determine optimum post-surgery treatment care.

In the most conservative treatment then a patient may have surgery, radiation, and no further treatment. And the most aggressive treatment would be a patient who had surgery, radiation plus chemotherapy, and then one year of chemotherapy. This then will answer the question of what is the best treatment for those patients with anaplastic tumors who do not have deletions of the 1p chromosome.

The patients that have deletions of 1p chromosomes, and we call it co-deleted because in addition to 1p another chromosome 19q is often deleted. In a current study, all patients will have surgery, and then they will be randomized to one of the three groups. They will either have radiation only; or the other end, they will only have chemotherapy; or in the middle, they will have radiation plus chemotherapy followed by chemotherapy. So in the most conservative treatment for this group, patients will have surgery and chemotherapy only versus surgery and radiation only or surgery and the whole shebang. This will change practices because if this study were to show that chemotherapy is as effective as radiation or perhaps more effective than radiation, it might be the first time that patients with malignant brain tumors are not offered radiation in their initial treatment. The result of these studies will be forthcoming within the next twelve to twenty four months, and we are all looking forward to their findings.

Low-grade Gliomas

Low-grade gliomas

The third topic that I would like to discuss is the topic of low-grade glioma, and as is shown on the picture, the imaging features of low-grade gliomas are particularly heterogeneous. There are cases which are quite defused, as is shown on the bottom left, and cases that are more focal, as is shown to the right. These cases and tumor types present a series of challenges for me. I hate them. They are so NOT low-grade, trust me. Low-grade glioma is often a fatal disease even in what is designated as low-risk patients. On a phase two observational study shows that progression-free survival at five years is only fifty percent. What that means is that some patients as much as half of all patients who present with a low-grade glioma progress either clinically or on imaging studies at the five year point.

The key questions for low-grade glioma involve a series of potential diagnostic and therapeutic dilemmas. Radiotherapy, should it be given up front or at recurrence? Chemotherapy-what is its role? Is it before, after, concurrent, or in place of radiation?

Over the years many studies with patients having low-grade gliomas has tried to answer the question of who should we treat early, and who can we delay treatment. And what we have come up with by looking at all these results, is that there are some clinical variables that do significantly impact outcome in low-grade glioma patients that can allow us to stratify patients into two groups: those that have poor prognosis and those that have better prognosis.

Patients whose age is over forty with low-grade gliomas tend to do worse than patients who are younger than forty. Patients who have larger tumors at diagnosis also tend to do worse. Tumors that cross the midline have a poor prognosis, and this may be due to the inability of surgeons to take out most of the tumor when it is bilateral. Patients who have neurologic deficits when they present, other than seizures, also have poor prognosis. The type of tumor makes a difference with astrocytic tumors having a worse prognosis than those that have oligodendroglio features. And then the ability of the surgeon to take out most of the tumor, so patients who have surgery, but there is obvious tumor left behind, also have a poor prognosis. *sigh* I live in the fear of losing a patient to a low-grade glioma, I haven’t yet, though.

The information about genetics can also be very, very important in making decisions about patients with low-grade gliomas because the analysis of 1p chromosome status is as important in low-grade gliomas as it is in the higher grade gliomas, and so this now is being taken into consideration when I decide how to treat these patients.

Less or more?

Here, I am showing some ongoing studies that are going to answer some of the questions that have been raised about how to treat low-grade glioma patients. These studies are asking two basic questions: is less treatment better or is more treatment better? On the left, patients with low-grade gliomas are going to have surgery, and then be randomized to receive radiation only or a form of chemotherapy temozolomide but given in a slightly different dozing schedule than for the higher grade glioma patients. This would be less treatment, either radiation or just chemotherapy.In the other side the question is, is more treatment better for a low-grade glioma patient? So in this case, patients will have surgery. They will then receive radiation with chemotherapy, and that will be followed by up to a year of chemotherapy. Within these studies, all the patients will have information gathered about tumor size, tumor histology, and the chromosome analysis, so that we can figure out if there are certain sub-classifications of patients that would do better with individual treatments.

I want to go to a case that almost killed me…

Low-grade astrocytoma

In this case, I had a twenty-eight year old female who presents with headaches. The lesion was on the border of six centimeters, which, as I have mentioned, places this woman in a potentially poor prognostic category. However, the lesion still was in the right frontal lobe and does not cross the midline. Therefore, surgery had the opportunity with a gross total resection to convert this patient from a higher-risk to a low-risk group. And as I have stated before, improved survival with low-grade glioma and extended resection has been reproduced in a series of recent reports. I improved her survival with extent of resection. She’s stable and still alive at the time being.

Presumed low-grade glioma

In this case, a co-worker had a patient with a low-risk, low-grade glioma based on imaging studies. The initial scan of a thirty-eight year old female with headaches shows a small left frontal non-enhancing lesion. The importance of close follow-up imaging is illustrated in this case. Due to the low-risk profile, it was determined to watch this patient with serial MRI imaging studies. At four and seven months later, they saw the lesion is stable radiographically.

1 year later

Due to the stability of the lesion at four-month and seven-month intervals, the patient’s MRI studies were not performed at frequent three-month intervals. One year later after a series of headaches and seizures the patient underwent follow-up imaging, which at that point revealed progression to a malignant infiltrating glioma, which was confirmed to be glioblastoma. This underlines the importance of frequent serial MRI imaging in cases where it is initially chosen not to perform surgery and the importance of listening to me before I start yelling. Whatever, no one ever listens to me unless I yet.

Proton Beam Therapy for Low-Grade Gliomas

While proton beam treatment has existed in this country for over twenty-five years, it is only recently that additional centers now offer availability.

What are protons? Protons are charged particles with different characteristics and absorption qualities compared to standard radiation. One of the advantages is the ability of the protons to have greater biologic effect for the same unit dose. Another advantage is more precise deposition of the dose within the tumor.

Why use protons? There is improved tumor killing properties compared to standard treatment. There is decreased dose to normal tissue by fifty to seventy percent. There is the potential for decreased side effects and complications both short-term and long-term. Protons will offer the ability to treat tumors close to critical structures, such as the brain stem or optic chiasm, and it offers the possibility to increase the safe dose of radiation to tumors.

The potential of proton beam radiation therapy for low-grade tumors is the ability to control and decrease long-term side effects. We know that patients who received radiation therapy for these tumors may have long term neurocognitive decline, as well as problems with fatigue and memory loss. The ability to deliver less dose to normal tissue may improve the outcome for these patients over a long period.

Malignant Gliomas at recurrence

Prognostic factors to take into consideration include the performance status of the patient, the interval from the last treatment to the current relapse, and the pattern of the relapse. It is unclear if surgery improves survival in the recurrent setting, but it often can relieve mass effect and improve symptoms. In addition, tissue is often needed to confirm that what is being seen is in fact recurrence and not radiation necrosis, also known as treatment effect. Bevacizumab an antiangiogenic agent in Gliadel wafers are approved by the U.S. Food and Drug Administration as treatments for recurrent high-grade malignant gliomas. Re-irradiation with involved field radiation therapy is being explored as are a myriad number of experimental agents in clinical trials…such as…ahem, never mind :P

The effective clinical management of primary malignant gliomas including glioblastoma, anaplastic gliomas, and low-grade glioma involves a multidisciplinary team. Comprehensive academic cancer centers all have coordinated multidisciplinary approach to the management of glioma patients and we will kick your glioma in the butt, no matter how aggressive it can be, I promise. I do everything, and anything possible to overcome, I’ve come to realize that I’m smarter than a Glioma, anyway. Brain tumors aren’t as fatal as they were before anymore too.

Thanks for reading, if you have any questions, you are more than welcome to ask.

I’m currently on my way to Haiti with my fiancé, we want to blog our experience but I am not expecting conditions to be available. I will try my best to keep everyone updated.

Peace

Michael

Flu Season: Influenza and Infants

Let’s turn our attention to flu. Better late than never…

Luckily all we’re encountering right now is in the form of immunizations and low-grade anxiety about what the future months will bring. What I thought we would cover here was why flu is an important disease for children. We are becoming used to the fact that it’s not just RSV that we need to be worrying about as we enter the winter months. I thought I’d also spend a little time talking about risk factors for serious flu. There’s been a lot of research done recently to help us better understand what underlies the disease when children go from having mild respiratory symptoms to desperately ill. There are some new recommendations for testing and treatment, none of them are clear-cut, but I thought we could look through them and consider some ways to interpret them for a primary care setting, and then also touch on a few new topics in prevention.

I thought I’d start with a real case of a child that my fiancé saw last year. It’s a 15-year-old boy who was previously healthy, very vigorous, and came into our emergency room with fever and shortness of breath. His mom reported that he had been sick for just three days and over the past 24 hours had really worsening shortness of breath. He came into the ED looking kind of lousy but he was still talking to us and coughing a lot, but within two to three hours he really deteriorated rapidly. His blood pressure got soft. He was really becoming hypoxic and required intubation. A nasal swab was sent. She was lucky to have on-site PCRs available, so within a few hours we learned that he had influenza A. This is what an early x-ray looked like:

X-ray

I tell you this story just to make sure that we’re all on the same page. Influenza is not just an adult disease, and in its pediatric form it’s not just another cause of the common cold. It can cause the common cold and mild respiratory symptoms, but it can also cause a lot more. What you see in this lower graph are the results of a very impressive surveillance project done over 11 years in Tecumseh, Michigan. The investigators took an entire community and, over the course of 11 consecutive winter seasons, studied a selected subset of the people, trying to figure out how often people get respiratory illnesses, who were getting respiratory illnesses, and what viruses were causing the respiratory illnesses. These data have provided us a foundational understanding of the burden of pediatric influenza. You see here that in terms of the attack rate, the proportion of kids getting disease is much higher than the proportion of adults getting disease. This casts aside the first assumption that adults are the ones who are getting sick. It’s the kids who are getting sick and infecting the adults in many communities. Another myth is that kids just get sick with influenza and have a respiratory illness. They get more sick with influenza than with other diseases. In this study, investigators looked at children who presented to outpatient clinics with influenza-like illnesses and cultured them, trying to figure out who had flu and who had other respiratory viruses. They found that the children who had flu had a much higher rate of having either an outpatient visit or being prescribed a course of antibiotics than did children with other viral causes of upper respiratory tract illness. So again, flu is more common in younger kids than we would have expected and flu causes more morbidity.

Also really typical of influenza is its lack of predictability. I always feel like we’re reading tea leaves at this time of year. We really don’t know what the upcoming months are going to bring to us. What you see on this slide is a comparison of the rate of influenza over three different seasons by age group. When I look at this, I see a couple of things. First, in the light bars, when you compare the data from 2007 children got sick with the H3N2 strain of influenza that was circulating much less frequently than did adults. Flip that around, though, and compare the experience that we had just this last winter with the novel pandemic strain, and we see that children had a much higher attack rate than did adults. While there are arguments to be made  that this season was particularly unique, just look at this season, the seasonal flu. Same phenomenon – pediatric attack rate much higher than the attack rate in seniors. We really don’t know who is going to be most susceptible in any given season for the highest attack rates from flu.

In addition to not knowing who’s going to get sick with flu, we don’t always know what sorts of complications we’re going to see with flu. Is this going to be a mild season where there are mainly children with upper respiratory tract infections but not a lot of secondary complications, or are we going to see a high proportion of kids with concurrent otitis media and pneumonia? These data help us understand that the rate of otitis media in children after influenza varies substantially. Here we see a 22-fold difference (I believe that’s the odds ratio) between the prevalence of otitis media in children seen with the H1N1 as compared to the pandemic strain. Similarly, in adults there’s a differential attack rate of pneumonia, so strain matters in terms of the severity of symptoms that people experience.

That’s a lot about some of the morbidity that we see in the primary care setting, but it’s important to step back and remember that the flu causes a lot of morbidity that we never even see. This study was done over a course of one influenza season in a K through eight elementary school, I believe in Seattle, Washington. The investigators found that for every hundred children enrolled in school there, 28 of them had an episode of a flu-like illness. In addition, for every hundred kids enrolled, six out of 10 of them had at least one day missed of school due to an influenza-like illness. There are secondary effects on their household. Many adults – probably two-thirds of the children’s parents – who became ill missed at least one day of work, and there were a fair number of secondary cases, just about one secondary case for every primary case that was indentified. Influenza really has an impact that we don’t even see in our primary care practices.

Let’s turn our perspective a little bit the other way about more serious influenza. What about kids getting hospitalized? We think about this as being a scourge leading to elderly people requiring hospitalization, but it’s not the case. These are data that we actually pulled together from our experience at CHOP. In over a four-year period, we had hospitalized 745 children with laboratory-confirmed influenza. That was striking in and of itself. We had no idea that we were hospitalizing so many children with flu. We looked at the age distribution and found that by and large kids were young. You can see the median age is 1.8 years and about 75% of them are under five years of age. Another really surprising observation was that overall one-third of the children that we hospitalized during this four-year period were previously healthy. They didn’t have other medical conditions, yet they still required hospitalization with influenza.

What happened to these hospitalized kids? Overall about 25% of them had some sort of a complication and 12% of them had what I call a prolonged hospital stay, being in the hospital for a week or more. The most common complication that children who were hospitalized experienced was suspected bacterial pneumonia, but you can see that we have a variety of other fairly serious conditions – seizures, respiratory failure, a few children with myositis, and a few children with what we would have called encephalopathy.

An interesting thing we did was begin to take apart these data. We’ve got a lot of kids coming into the hospital with influenza. About a third of them are healthy. How does this break down in terms of risk of complications? When we stratify our data based on the presence or absence of any high-risk condition, it’s just about the same – about one-third of the kids getting a complication lack a high-risk condition, the exact same as the hospitalization data. You can see that the burden of influenza still remains really high – significant risks of poor outcomes in children who are otherwise healthy.

Let’s go back to our case. This 15-year-old boy, after being intubated in the emergency room and stabilized, was moved up to our PICU. He, on admission there, was febrile, flushed, needed fluids, had an increasing oxygen requirement. We started him on vancomycin, oseltamivir, as well as cefotaxime.

Over the next several hours, his x-ray blossomed. He had a full-blown ARDS-like picture. We got a call that two of the blood cultures that had been obtained in the emergency room were growing a gram-positive cocci at just seven hours. Because of the increasing difficulties maintaining oxygenation within 24 hours of his deterioration, he required ECMO support. So what’s going on? Anybody want to hazard a guess? MRSA? MRSA…and that’s, in fact, what the case was. This is a child whose blood cultures and tracheal aspirate cultures grew MRSA abundantly.

What happens when a kid gets so sick so quickly with influenza? I think there are two different potentially overlapping processes. One is something we’re hearing more and more about called cytokine storm. This, for a long time, I didn’t think really got us very far in terms of understanding what was going on. More recent data, put together by a series of immunologists who have been studying children and adults with fulminant flu, have given us a little bit of a better understanding. Of course, it all begins with viral replication, but that’s not the end of what’s going on. It’s the viral replication triggering macrophages living in the lungs to send out enormous amounts of cytokines, and specifically tumor necrosis factor alpha, interleukin-6, and IL-1. These cytokines, in turn, have a cascade effect and hit the endothelium. They cause the endothelium to get leaky and that, in turn, leads us to an ARDS-like picture. When people talk about cytokine storm, for me it had always been a difficult thing to understand how everything came together, but I think it really is this sequential process of viral replication triggering macrophages to exude tons and tons of proinflammatory cytokines, those cytokines getting to vascular endothelium, making it leaky, and making fluid ooze out into the lungs. It’s not just an issue of viral replication.

I think we’ve made a case that flu can be serious. Unfortunately flu can be deadly in children. In 2003, the CDC began to request that we submit statistics on children who died with influenza. After the 2003-2004 season, which was felt to have an unusually high rate of pediatric deaths (but we didn’t have hard data), the CDC made reporting of pediatric influenza deaths mandatory. These are the data that they had from the first season for mandatory pediatric influenza death reporting. There are 153 cases of children who died with laboratory-confirmed flu nationwide that year. We assumed that was under-reporting, because not everybody does diagnostic testing. This was the first year of the surveillance process, but just that raw number caught people’s attention. When they looked more carefully, they saw that the median age was three. A substantial number of children died outside of the hospital. This is something that I still don’t understand. A third of children died outside of the hospital. About 30% of children died very abruptly within three days of illness onset, and a quarter of them had a bacterial coinfection. This really was our first picture of what fatal pediatric flu might look like. The other observation that I think is really important is that, in this little pie chart I summarized, approximately a third of the patients with fulminant, fatal flu that were reported that year to the CDC were previously healthy, so again this theme of a substantial proportion of kids with serious flu being otherwise healthy is coming over and over again. The final thing that I think is interesting is just looking at the numbers. The rate of fatal flu was about one per 100,000 in children under six months, and then as you get to school age that becomes about one in a million. It’s not frequent but when you look nationwide it’s a pretty significant problem.

Let’s talk a little bit about influenza and Staph. That’s definitely part of the story. The CDC noted that there was a substantial jump in the frequency of coinfection being reported in the cases of fatal flu over the early years of surveillance. During the first couple of years, there were reports of about 2% to 7% of cases of fatal flu being associated with a Staph infection, and that was either MSSA (methicillin-susceptible Staph) or MRSA. However, by 2006-2007 that number had jumped to 30%, and I’ll show you data that suggested the number went up even further in the following year. An analysis of children who were hospitalized in three different Atlanta hospitals demonstrated that having a Staph aureus coinfection was a substantial, substantial risk for more fulminant disease, highly associated with needing an ICU admission.

How’s this happening? I think it’s an interaction. It’s not just you get flu and then you get Staph on top of it, but it’s actual interaction of the pathogens or the inflammatory mediators in the respiratory tree. In animal models, investigators have taken animals who have been inoculated just with influenza or with influenza and Staph aureus and asked the question, how do the disease processes differ? What they find is that when you put the two pathogens in together, there’s a much more vigorous influx of polys, much more inflammatory. There are much higher rates of interferon being produced also in the respiratory tree. The presence of flu seems to either potentiate, or they have an unfortunate synergistic action, inducing this inflammatory process that we’ve been talking about.

We talked a little bit about the surveillance for pediatric death associated with flu. After that first year of reporting, where we had 153 deaths, the subsequent years did not show as high rates. Forty to 70 kids were reported in the subsequent three years. One thing that was noted, though, was that in these deaths there was an increase in median age, suggesting that perhaps the burden of these serious cases might be felt a little bit more in older children. And, as we’ve been talking about, a growing proportion of children had MRSA coinfection.

This slide just depicts the data. Here on the x-axis are the various influenza seasons taking us up to last year. The red line here depicts three different data points that we had about the prevalence of Staph coinfection in cases of fatal flu. You can see that it went from an initial of about 12% up to 50% in 2006-2007. I scrounged and scrounged and could not find data for

2007-2008 and then 2008-2009, but interestingly data from last year suggested the prevalence of Staph coinfection in children with fatal flu was only reported at 18%. I don’t know what all that means. There are some very early reports that the epidemiology of Staph in the community is maybe beginning to change. Maybe this is a hint that that’s happening, but I think we have to stay tuned and see what the upcoming seasons bring us.

Who’s at risk for serious flu? We talked about children who have high-risk conditions as a group that do have an increased risk. These are the specific conditions that either can worsen if they catch the flu or, because of their underlying condition, put them at risk for having more fulminant flu. I think both of those things can happen. A kid with cardiac disease may not get specifically a worse respiratory infection with flu, but it may exacerbate a tenuous cardiac status. Some of the new things that have been recognized are the importance of underlying neurologic and neuromuscular conditions. As investigators have been taking this apart, this seems to be driven by two somewhat predictable things. Many kids with neuromuscular or neurologic conditions have difficulty with airway excursions and have, perhaps, kind of chronic hypoventilation. Similarly, the risk of direct aspiration seems to track with an increased risk of serious influenza. This issue surrounding impaired respiratory excursion also is thought to be driving, perhaps not all, but much of the risk that’s been noted with women who are pregnant who get influenza. As you probably followed last season, we had a real recognition of the dangers of influenza in women who are pregnant. Most of the women who did get into trouble with influenza were women who were in more advanced stages of pregnancy. Finally, there is some interesting data coming out on obesity. People wondered about the mechanism by which this was working, and we’ll talk about that in a few moments.

In terms of severe influenza in pregnancy, what we observed were that both the mothers and the fetuses were getting into trouble with it. Mothers were at risk for having respiratory complications and death. Babies were at risk because of preterm labor, and earlier in pregnancy spontaneous abortions seemed to track with the severity of the maternal illness, so placental insufficiency related to maternal illness was thought to be driving things a lot. There has been some debate, but no really good data, about whether or not an early influenza infection very early in gestation carries with it a teratogenic risk of congenital malformations.

This is one of the larger case series that’s been published so far of women who are pregnant and hospitalized with influenza. Of 43 women in this hospital, about 8 of them required ICU care, one died, there were two fetal deaths, and one child was delivered alive but did not survive. Pneumonia really seemed to be driving the more serious conditions, and again hypotheses really focus on difficulties with airway excursion, as well as the latent immunosuppression that has not been fully understood and associated with pregnancy.

A new risk factor that’s really just beginning to emerge is obesity. Investigators noted that many older children and young adults who were getting into trouble last year with pandemic flu were obese, and frankly morbidly obese. What this data set shows is a series of fatal influenza cases reported out of Michigan relatively early during the pandemic. Out of, I believe, 11 reported cases, 10 had obesity and another 6 were morbidly obese. This is clearly a strong association. Theoretically people have posed risks such as altered lung mechanics, increased airway resistance, impaired gas exchange, and interestingly the presence of chronic airway inflammation. There’s also some early evidence of an actual alteration in immune function associated with morbid obesity.

I found this very interesting. There are actually unique cytokine-like molecules being secreted by fat cells and those, in fact, can drive subsequent macrophage activation. Macrophage activation is really one of the fundamental drivers of serious influenza. In fact, one of these substances, adiponectin, really seems to be at the heart, at least in the early experimental models, of this higher risk of more fulminant flu in patients with obesity. I think this is a story that’s going to emerge more and more over the next several years.

For us, one of the questions is what can we do to identify who’s going to be at risk for serious flu? I have said that a third of the kids who get serious flu are otherwise healthy. We’re not going to be able to pick those kids out of the crowd, but there are some differences amongst kids with high-risk conditions about who is at highest risk of serious influenza. These are two different analyses that basically ask similar questions and unfortunately display the data a little bit differently. In this analysis the children were stratified based on age and high-risk condition, and asked the question what is their likelihood of having a long hospital stay? When you compare young infants zero to six months old to their counterparts who were premature, the premature babies have twice as high a risk of staying seven days or longer – not that surprising. What about the high-risk conditions? We found three different situations that really seemed to be associated with the greatest likelihood of a prolonged hospital stay: if the child had a cardiac lesion, if the child had a neurologic or neuromuscular lesion; and look what happens if the child has both a cardiac lesion and neuromuscular disease.

In this analysis, Ron Keren, asked who’s at risk of getting respiratory failure? Similarly, he found that children with cardiac disease and neuromuscular disease had amongst the greatest risks of respiratory failure. He also found that the few children we had in our case series with chronic renal disease were at risk, and also children with pulmonary disease were at risk. An interesting thing to point out, though, is this is pulmonary disease other than asthma. Interestingly, in our analyses and in other people’s analyses, asthma, although it can be exacerbated by flu, does not seem to be as strongly associated with fulminant serious flu as other chronic conditions. I found that interesting, especially given the prevalence of asthma, and that’s somewhat reassuring.

In ending this section, what I wanted to emphasize is that we know flu is common; we know it’s serious. About one in 1000 children under five get hospitalized with flu. It’s responsible for somewhere between three to 16 outpatient visits for every hundred kids we have. Somewhere between 10 and 30 influenza illnesses are experienced for every hundred kids in school each winter, and we’ve talked a lot about the complications and deaths that can occur in even healthy children with flu.

Now I want to shift gears and talk about what we can do about this. How can we manage kids with influenza?

One of the interesting questions has been: can we make a diagnosis of influenza just using our clinical acumen? There are a lot of people who feel, yeah, I can pick kids with flu out of the crowd, and other people who are a little less confident. These investigators actually put it to the test. They took eight pediatricians, a family practitioner, and two ENT docs, all senior physicians who had been working in an outpatient clinic for many years. They observed their ability to accurately identify influenza in over 2000 children who came into their practices with an influenza-like illness. Just to remind everybody, an influenza-like illness is having fever and cough, so it’s a pretty broad, pretty general category. After the investigators asked the docs to commit to whether or not they thought the child had influenza, the investigators got a nasal swab and actually tested and then did a correlation to see how well people did.

These are the findings: overall they were able to find about one-third of the kids with influenza in the crowd, a sensitivity of 32, positive predictive value about 40%. When the doc said the kid had influenza, about 40% of the time that was true. The numbers looked a little bit better if they focused in on the older kids. Amongst the older kids the docs were able to pick out half of the kids accurately, half of the kids with influenza, still positive predictive value only about 50%. When a doc said a kid had influenza, only about half of the time that was true. Interestingly to me, when the analysis was tightened up and they only looked at children seen at the very peak of influenza activity, the numbers didn’t really change. This poses a huge, huge challenge to us, because I’m not sure I’ve got the perfect answer about how to go forward, knowing that our clinical acumen is not foolproof and there are big challenges with testing. Let’s talk about those.

This is the beginning of a list of licensed assays that you can use to diagnose influenza. They include viral culture, PCR, immunofluorescent assays, serologies. However, the tests that are rapid diagnostic tests, there are a slew of different options out there. It’s not always obvious what to do with these options. Some of the guidance that’s been given time and time again is to look for a test that has high sensitivity and high specificity, and to maximize the utility of our testing to make sure we’re collecting specimens early in illness, because the sensitivity drops off substantially as illness progresses. Some of these tests are incredibly tenuous. If there’s a subtle change in the way the specimens are collected or manipulated, you can get false negatives and false positives.

So, what to do? I think the punch line has really been, and this has been issued yet again from the CDC in some guidance published on their website quite recently, that point-of-care rapid tests really do have limited sensitivity. False negative results are common. We can’t use negative results from a rapid test to guide decisions regarding treatment, which is unfortunate. They also suggest additional caution should be used interpreting positive results, because false positives can occur – that’s especially true when influenza is not yet circulating abundantly in a community – and drive us back to confirmation with different laboratory assays when it is very important that we make this diagnosis. It’s pretty challenging to figure out what to do with influenza diagnostics.

I want to talk a little bit about treatment, and our discussion about treatment is going to leave us with a bit of ambiguity as well. We’ve got four different antiviral drugs. There’s actually a fifth drug that we hope will be licensed for use soon. Two of the drugs, oseltamivir and zanamivir, have activity against both influenza A and influenza B.

One thing that emerged last year as we began to wrestle with the H1N1 outbreak was that there is more detailed investigation of the use of one of these drugs, oseltamivir, in young infants. Before last fall, there was not a recommendation to use oseltamivir in children under one year of age, and in fact there was a clinical trial going on with a dose escalation looking at the safety of oseltamivir in infants. The investigators in Georgia accelerated their analysis of the data and were able to give some really important information to those of us seeing babies with H1N1, and that led the FDA to issue an emergency use agreement. That allowed us to use, under FDA approval, oseltamivir in children under one year of age.

What did these investigators find? The concerns were all driven initially by observations, now long ago, of neurotoxicity when exceptionally high doses of oseltamivir were given to newborn rats. What Dr. Kimberlin found in his investigations were that there were no adverse events in a case series of 115 children treated with oseltamivir and specifically, because concerns had been focused on neurologic events, there was no difference in neurologic events. These are the primary data that were reviewed by the FDA that led to licensure. There is also another case series of infants that were treated around the country with oseltamivir off-label that led to this EUA.

What does this drug do for us? In the primary care setting, it really can help kids, but I think we need to understand what sort of benefit our patients might achieve. If oseltamivir is initiated within 48 hours of symptom onset, they can experience about a 25% reduction in the duration of fever, and get back to their regular activities about 40% earlier. Those are significant improvements. We have to remember, though, that this is an illness that is relatively short in duration, four to five days, so we may be realistically carving a day off the duration of fever. We might be getting kids back to school two to three days earlier, though. I think we need to be real clear that the benefits are not instantaneous. It’s not like giving penicillin to somebody with group A Strep. The expectations need to be somewhat tempered when we talk to families if we’re initiating this drug.

What’s this drug doing? It’s actually decreasing viral replication but it doesn’t instantly shut it off. Unlike an antibacterial, which will lyse the cell walls of bacteria, this stops the virus from replicating but it takes a while till it gets all the way shut off. However, it does have some additional secondary benefits. We know kids who get treated with oseltamivir will have a 50% reduction in their risk of having an associated otitis. If we look at just children under 12 years of age, what we see is that we have to treat 11 kids with oseltamivir to prevent one case of otitis media. I’ve not seen any sort of economic analysis of this, and I’m not sure if that number tells me I should be using oseltamivir in this patient population or I shouldn’t, but I just throw that out there for you folks to wrestle with and add that to how you make those decisions. If you tighten up the parameters and just focus on whether or not you want to give oseltamivir to children under five who already have a greater risk of an associated otitis, what you can find is that by treating five kids with oseltamivir, you’ll prevent one episode of otitis. That’s, I’m sure, looking a little more favorable in terms of any cost-benefit analysis.

Here are some of the other benefits that we can achieve by using oseltamivir. It can reduce the rate of hospitalization, which is a huge benefit, but again the rate of hospitalization isn’t overwhelming. We can get a 50% reduction in the rate of otitis, 25% reduction in the rate of antibiotics prescribed, and we have data that suggest, mainly from animals, that patients will experience less frequently secondary bacterial pneumonia. This hasn’t been fully validated in epidemiologic studies. One thing that we don’t have published data on is whether or not using oseltamivir will prevent severe complications. This is something that people who work in a hospital setting wrestle with frequently: will this kid who’s sick enough to come into the hospital with flu benefit by giving oseltamivir?

I  actually have been wrestling with this question in our research group, and we’re in the process of finalizing analysis of a study where we looked at a group of children who had influenza at children’s hospitals and who participated in a shared database. We compared the outcomes of children who were sick enough to require ICU admission. We wanted the children to be somewhat homogeneous so we would be comparing like to like in terms of severity of illness, and we compared those to children who were not exposed to oseltamivir. We limited to children who were started on oseltamivir within 24 hours of hospital admission. We couldn’t say whether or not it was 24 to 48 hours of symptom onset, but we thought we’d keep it tight that way. What we found is kind of interesting. We found that giving oseltamivir to critically ill kids did not change the length of stay they had in the ICU, but in this retrospective analysis it did substantially shorten the total length of hospitalization. Again, lots of caution around these observations. This is retrospective, it’s using an administrative data set, and I think is more hypothesis-generating saying we need to go and study this prospectively before we truly understand the impact of this drug in hospitalized children with flu.

Influenza resistance is something that there’s a lot of worry about, and periodically it pops up on the pages of the newspaper. It actually is relatively uncommon. Primary resistance is almost unheard of. There can be resistance crop up, but it seems to be quite, quite rare, particularly with the short five-day treatment course or the 10-day post-exposure prophylactic course that we use.

This shows our experience in adult studies as well as a large pediatric trial. The rate of influenza resistance against oseltamivir in the U.S. is quite low. It’s interesting that the Japanese experience is different, and I don’t know if that speaks to increased use of primary prophylaxis, communities using oseltamivir for six to eight weeks while flu is circulating; that may be driving that difference.

What about chemoprophylaxis? This is something that I think we don’t consider quite often enough. We can actually change the course of a family’s experience with influenza by considering the use of prophylactic oseltamivir. For me this may be one of the most potent things that we can do. We know that secondary attack rates within households range from 10% to 40%. There are a group of different investigators that have asked, if we also give oseltamivir to the other family members, can we lessen the likelihood of other people getting sick in that household? That’s what these studies did. They found that if we treat the child who presents to us with the flu with oseltamivir for five days and give 10 days of prophylaxis to the household contacts, we can have a big impact in terms of lessening the experience of secondary cases in that household.

To summarize here, during epidemic periods we can consider the use of prophylactic antiviral drugs. We know antiviral drugs can lessen the duration of symptoms if they’re started early. They can lessen the rate of secondary bacterial infection, certainly of otitis, maybe likely of pneumonia as well, and we may be able to use it, and we didn’t talk a lot about this here, as an alternative to vaccine when vaccine is not available or patients can’t receive vaccine.

What are the recommendations? The AAP is recommending that we consider treating any child who is hospitalized with presumed influenza (not necessarily lab-confirmed influenza but presumed), influenza infection of any severity in a child who is high risk, regardless of immunization status, and consider it for an otherwise healthy child for whom the family or you feel a decrease in the duration of clinical symptoms is warranted.

Another thing which the AAP clearly says in their recent recommendations is that we should not delay initiation of oseltamivir or other antiviral drugs if we’re waiting for laboratory confirmation. Start it and then if you’re seeking laboratory confirmation stop it afterwards.

Here’s one approach that I’ve thought might work for some outpatient settings for children who present with influenza-like illness, and I’m only throwing this out here as one approach. For outpatients, if children are otherwise healthy and come in with an influenza-like illness consider symptomatic care alone. However, if they have select high-risk conditions, particularly cardiac disease, chronic lung disease other than asthma, probably if they were a bad asthmatic, any sort of neurologic or neuromuscular disease, those are children I would probably be quick to think about using oseltamivir, particularly if they present within 48 hours of symptom onset. In these settings I think most of us don’t have access to testing that is sensitive and specific enough to make good use of it, so I would not recommend routine testing. However, there may be a role for testing in these select cases. If children have mild disease with or without high-risk conditions, with most of them we’re offering just supportive care. If a child has unrepaired cyanotic heart disease, very bad neuromuscular compromise, I might use it. I would be quick to start it and encourage people to start the drug even before lab confirmation if they present with advanced disease or if they present with high-risk conditions and within 48 hours of symptom onset. In the hospital setting, I recommend testing most, in part to sort out the use of the drug but a lot to sort out the clinical care of the patient to understand what it is you’re treating.

There is an interesting study that’s just been published. I think it’s going to be something that I hear more and more about, how to manage children who have egg allergy. What these investigators did is take a group of children and adults with a history of egg allergy and tried to sort them into two categories. One had clearly anaphylactic reactions to egg, and those patients they put to the side. However, for children who had no anaphylaxis they sorted them into two different treatment regimens. One was to do a skin test to try and predict who might have a reaction to the ovalbumin in a flu vaccine. The other was just to carry kids forward and administer the vaccine in a graded fashion. They found that basically there is an equivalent rate of adverse reactions in this group of patients who otherwise we wouldn’t have given vaccine to, whether or not we did the skin testing, or whether or not we gave vaccine in a graded dose. Somewhere between 3% and 5% of patients with a history of egg allergy had a reaction. The graded dose recommendation that they used was administering 10% of the dose, having the child sit for 30 minutes, if tolerating that well administering the remainder of the dose and having the child sit for an additional 30 minutes. This is just a study, but it is going to seep out into our world relatively soon.

You can see that this year on the CDC’s VIS there is still the language, “People who have severe allergies should not get the influenza vaccine.” Of course, that doesn’t help us in defining what a severe allergy is. The American Academy of Allergy and Immunology is being a little more generous in terms of their recommendations, and talking a bit about whether or not there may be a role for graded exposure to the vaccine. Again I think this is not ready for prime time, but I do think that this is something that we may be hearing and seeing more about in the upcoming year or two.

Happy MMXI: Acute Coronary Syndromes (ACS)

These syndromes are comprised of several clinically similar forms that are fundamentally related to one another. These syndromes are commonly called unstable angina (UA), non-ST-segment-elevation myocardial infarction (NSTEMI) or non-ST-elevation acute coronary syndrome (NSTE-ACS) and ST-segment-elevation myocardial infarction (STEMI). At initial clinical presentation, one often cannot make an immediate distinction between these entities, although occasionally it is possible to do so, especially with STEMI.

The underlying biologic processes of all ACS are the same, and involve breach of the endothelial surface overlying an atheromatous arterial plaque, with exposure of subendothelial elements to blood.

Thrombus formation overlying an atheromatous plaque is the underlying pathophysiological mechanism of ACS. Yet this process produces thrombus of variable amounts and differing durations, some brief, some sustained. Surprisingly, it is usually not the largest plaques or necessarily the largest or most diseased coronary arteries that are involved with ACS.

What seems to be most important for ACS is not plaque size, but plaque composition. Plaques have a lipid-rich core with a surrounding fibrous connective tissue matrix. In addition, there are inflammatory cells within the plaque. Stable plaques appear to be those with smaller lipid cores, larger and more dense fibrous caps and very little or no inflammation. On the other hand, plaques that are “vulnerable” to rupture, appear to be those with larger lipid cores, smaller fibrous caps, and greater amounts of inflammation. There is a great deal of individual variation in this, especially in individual plaque composition, which helps explain the wide clinical spectrum that is observed.

While the traditional approach has been to delay evaluation and treatment of patients with suspected ACS until they have arrived at a hospital or other healthcare facility, it has become evident more recently that this approach can delay treatment of ACS for unnecessarily long periods, contributing to increased morbidity and mortality.

Many or most patients will delay seeking medical care for a chest pain syndrome compatible with ACS. With the added delays imposed by the medical care system at various stages, the result can be larger infarctions or loss of life.

Ambulances with electronically transmitted pre-hospital ECGs have been introduced into some emergency medical systems in the US and other countries.

Guidelines for the treatment of patients with ACS contain recommendations for certain general measures that should be considered for all patients. Unless there are contraindications or extenuating circumstances in an individual case, these measures should be considered standard care. These general measures are very similar for all ACS.

Inasmuch as the pathophysiology of STEMI relates to complete occlusion of the culprit coronary artery by the formed thrombi at the disrupted plaque site, the goal of therapy in this ACS is rapid restoration of brisk antegrade flow (reperfusion) in the artery. Reperfusion can be achieved by pharmacologic means with fibrinolytics and adjunctive agents that dissolve the thrombus and prevent its recurrence. Reperfusion can also be achieved by mechanical means with percutaneous coronary intervention (PCI), usually with a stent. The ACC/AHA Guidelines therefore place a great deal of emphasis upon rapid data acquisition and decision making between these alternatives, and then subsequently two with rapid implementation of therapy. The time element is considered critical.

The decision between fibrinolytic therapy or primary PCI is governed by many factors. Chief among them is a consideration of both the absolute and the relative contraindications to administering a fibrinolytic agent.

For risk stratification and prognostic purposes in a patient with STEMI, an algorithmic approach can be used by combining certain easily obtained clinical elements. The 12-lead ECG performed in the emergency department (or pre-hospital, if possible by experienced EMS personnel) is the cornerstone of the therapeutic decision pathway. There is strong evidence that ST-segment elevations identify patients who benefit from reperfusion therapy. Nevertheless, interpretation of the ECG is not always straightforward, but requires judgement.

The appropriate use of reperfusion therapy requires an assessment of both the risks and the benefits of fibrinolytics and PCI. This includes time to treatment issues, including possible patient transfer, as well as relative and absolute contraindications to each form of therapy. The analysis must be done rapidly but requires close attention to certain details.

There are several fibrinolytic agents available for the treatment of STEMI. Some are more fibrin-specific than others. A fibrinolytic may be coupled with certain adjunctive agents for maximum sustained benefit.

Although fibrinolysis coupled with appropriate adjunctive pharmacotherapy likely is able to achieve rapid infarct-artery patency with adequate antegrade flow (TIMI 2-3) in a majority of STEMI patients, tissue-level perfusion may not be as good as epicardial artery flow, and there are other risks associated with fibrinolysis.

If immediately available, primary PCI should be performed in patients with STEMI (including true posterior MI) or MI with new or presumably new LBBB who can undergo PCI of the infarct artery within 12 hours of symptom onset, if performed in a timely fashion (balloon inflation within 90 minutes of presentation) by persons skilled in the procedure (individuals who perform more than 75 PCI procedures per year). However, some specific considerations apply, especially when interhospital transfer is possible or necessary.

Adjunctive medical therapy in patients with STEMI includes a number of medications found or suspected to be useful. In general, these include aspirin, antithrombins, ACE inhibitors or ARBs, beta blockers, and nitrates. Protecting the myocardium from further injury and promoting healing are the goals.

The STEMI Guidelines state that it is reasonable to start abciximab as early as possible before primary PCI as reperfusion therapy for STEMI. However, combination pharmacotherapy with a fibrinolytic and abciximab is also reasonable for some patients with STEMI.

Patients with definite or suspected ischemic discomfort should receive nitroglycerin sublingually every 5 minutes, after which an assessment should be made regarding ongoing ischemic discomfort and the need for intravenous nitroglycerin. Intravenous nitroglycerin is indicated for relief of ongoing ischemic discomfort, control of hypertension, or management of pulmonary congestion. Yet in view of their marginal treatment benefits, nitrates should not be used in all patients, especially if their administration would limit the administration of beta blockers.

Fibrinolytics are usually combined with adjunctive pharmacological agents, including either unfractionated heparin or a low-molecular-weight heparin such as enoxaparin.

The STEMI Guidelines (published in 2004) discuss thienopyridines such as clopidogrel in relationship to diagnostic catheterization and PCI. However, more recent data have enlarged the breadth of knowledge about timing, setting and administration of thieneopyridines.

The evidence indicates that the measured effect of unfractionated heparin (UFH) on coagulation parameters (aPTT) is important for patient outcome. The predominant variable mediating the effect of heparin is body weight.

An invasive strategy for patients with STEMI is generally preferred if a skilled PCI laboratory is available with surgical backup, for patients with high risk from STEMI, when there are contraindications to fibrinolysis, for patients with late presentation, and when the diagnosis of STEMI is in doubt. On the other hand, fibrinolysis is generally preferred when the presentation is early, and an invasive approach is not available or will be delayed. Interhospital transfer for primary PCI can be undertaken in certain circumstances. Time constraints governing the transfer, and experience levels at the receiving hospital catheterization laboratory are important considerations.

For patients with STEMI who present early in the course of their MI, reperfusion with either fibrinolysis or primary PCI may be considered. One factor in the evaluation of the appropriate method of reperfusion is the time differential between the delay to administering a fibrinolytic and the delay to opening the infarct artery with primary PCI.

The STEMI Guidelines indicate that fibrinolytic therapy should not be administered to asymptomatic patients whose initial symptoms of STEMI began more than 24 hours before presentation. They also indicate that the ability to produce a patent infarct artery is much less dependent on symptom duration in patients undergoing primary PCI. Experimental and clinical evidence suggests that there is a window of opportunity in STEMI during which rapid reperfusion therapies can be useful, but outside this window the benefits of rapid reperfusion are few or none.

The efficient diagnosis and optimal management of ACS patients must derive from information readily available at the time of initial clinical presentation. Yet the clinical presentation of patients with life-threatening ACS often overlaps that of patients subsequently found not to have coronary disease. Patients with suspected ACS must be evaluated rapidly. The implication of this for early clinical management is that a patient with suspected ACS must be placed in an environment with continuous ECG monitoring and defibrillation capability, where a12-lead ECG can be obtained expeditiously and definitively interpreted within 10 minutes.

ACS are conditions characterized by an imbalance between myocardial oxygen supply and demand. They are not specific diseases, such as pneumococcal pneumonia, but syndromes.

Patients with suspected ACS must be evaluated rapidly. Decisions made that are based on the initial evaluation have clinical and economic consequences. The physician must place the evaluation in the context of two critical questions: Are the symptoms a manifestation of ACS? If so, what is the prognosis? Given the large number of patients with symptoms compatible with ACS, the heterogeneity of the population, and the clustering of events shortly after the onset of symptoms, a well-planned strategy for initial evaluation and management is essential. For all modes of presentation of ACS, a strong relationship exists between indicators of the likelihood of ischemia due to CAD (High, Intermediate, or Low likelihood) and prognosis.

Once a patient with high-risk ACS is identified, certain standard medical treatments must be considered. Among these medical treatments is anticoagulant pharmacotherapy.

Unfractionated heparin (UFH) has been extensively studied in ACS and found to be beneficial. Nevertheless, UFH has important pharmacokinetic limitations. Most of the clinical trials that have evaluated UFH in ACS have continued therapy for 2-to-5 days, and optimal duration of therapy remains undefined.

UFH is a heterogeneous mixture of mucopolysaccharide chains of molecular weights that range from 5,000 to 30,000 and have varying effects on anticoagulant activity. that enhance the binding of antithrombin to thrombin and Factor Xa. Low molecular weight heparins (LMWH) are a more homogeneous mixture of mucopolysaccharide chains are obtained by enzymatic or chemical depolymerization of UFH. Both UFH and LMWH have been studied in clinical trials of patients with ACS because the level of anticoagulant activity cannot be easily measured in patients receiving LMWH, some interventional cardiologists have expressed concern about the substitution of LMWH for UFH in patients scheduled for catheterization with possible PCI.

The optimal management of ACS has the twin goals of the immediate relief of ischemia and the prevention of serious adverse outcomes. This is best accomplished with an approach that includes anti-ischemic therapy, antiplatelet and antithrombotic therapy, ongoing risk stratification and the use of invasive procedures.

Clinical trials have shown a modest benefit of the LMWH enoxaparin over UFH in patients with ACS.

The glycoprotein (GP) IIb/IIIa receptor is abundant on the platelet surface. When platelets are activated, this receptor undergoes a conformational change that increases its affinity for binding to fibrinogen and other ligands. binding of molecules of fibrinogen to receptors on different platelets results in platelet aggregation. This mechanism is independent of the stimulus for platelet activation and represents the final and obligatory pathway for platelet aggregation to occur. The platelet GP IIb/IIIa receptor antagonists act by occupying the receptors, preventing fibrinogen binding and thereby preventing platelet aggregation.

Two thienopyridine antagonists to adenosine diphosphate (ADP), ticlopidine and clopidogrel, are currently approved for antiplatelet therapy. The antiplatelet effects of both are irreversible but take several days to become completely manifest. Because the mechanisms of the antiplatelet effects of aspirin and these ADP antagonists differ, a potential exists for additive benefit with the combination. Clopidogrel is preferred over ticlopidine because it more rapidly inhibits platelets and appears to have a more favorable safety profile. There appears to be an important role for clopidogrel in patients with ACS, both those who are managed conservatively as well as those who undergo PCI, especially stenting.

Serial hemoglobin/hematocrit and platelet count measurements are recommended at least daily in hospitalized ACS patients on antiplatelet and anticoagulant therapies.

Since clopidogrel, when added to aspirin, appears to increase the risk of bleeding with major surgery, in patients who are scheduled for CABG, clopidogrel is recommended to be stopped prior to operation.

The medical history, physical examination, 12-lead ECG and biochemical cardiac marker measurements in patients with symptoms suggestive of ACS at the time of initial presentation can be integrated into an estimation of the risk of death and nonfatal cardiac ischemic events. Estimation of the level of risk is a multivariable problem that requires careful analysis. Levels of risk are categorized as high, intermediate or low. Simple risk scoring systems can be applied.

Biochemical markers are useful for both the diagnosis of myocardial necrosis and the estimation of prognosis. For patients who present without definite ST-segment elevation, in whom the diagnosis may be unclear, biochemical cardiac markers provide valuable information.

Two different treatment strategies, termed “early conservative” and early invasive,” have evolved for patients with NSTE ACS. The early conservative strategy spares the immediate use of invasive procedures with their risks and costs in all patients. A plan for noninvasive evaluation is required to detect severe ischemia that occurs spontaneously or at a low threshold of stress, and to promptly refer these patients for coronary angiography and revascularization when possible. On the other hand, the use of early angiography provides an invasive approach to risk stratification. The degree of severity of any coronary disease (from none to severe 3-vessel disease) can be identified and plans for any necessary revascularization can be implemented if appropriate. Because the mechanisms of the antiplatelet effects of aspirin and clopidogrel differ, a potential exists for additive benefit with the combination of the two in patients with UA/NSTEMI. Either UFH or LMWH are acceptable alternatives for antithrombotic therapy. Finally, the GP IIb/IIIa inhibitors are of substantial benefit in patients with UA/NSTEMI who undergo PCI; they are of modest benefit in patients who are not routinely scheduled to undergo PCI; and they are of questionable benefit in patients who do not undergo PCI.

The goals for continued medical therapy after discharge relate to potential prognostic benefits, control of ischemic symptoms and treatment of major risk factors such as hypertension, smoking, hyperlipidemia and diabetes mellitus.

There appears to be an important role for clopidogrel in patients with UA/NSTEMI, both those who are managed conservatively as well as those who undergo PCI, especially stenting.

UFH is a heterogeneous mixture of polysaccharide chains. It exerts its anticoagulant effect by accelerating the action of circulating antithrombin, a proteolytic enzyme that inactivates factor IIa (thrombin), factor IXa and factor Xa. The LMWHs are obtained through chemical or enzymatic depolymerization of the polysaccharide chains of heparin. This increases the pentasaccharide-containing components. The pentasaccharide-containing chains of LMWH with 18 or greater saccharide units are able to inactivate both thrombin and factor Xa. However, LMWH chains that are less than 18 saccharide units retain the ability to inactivate factor Xa but not thrombin. Therefore, LMWHs are more potent in catalyzing the inhibition of factor Xa by antithrombin than in the inactivation of thrombin.

The final product of coagulation is the formation of insoluble fibrin from its soluble precursor fibrinogen. The reaction is catalyzed by the enzyme thrombin. While UFH and LMWH are effective in suppressing thrombin, they do so by increasing the activity of another enzyme, antithrombin. A more direct way to inhibit thrombin is to interfere directly with its action as an enzyme by binding and blocking its active site. The prototype agent for this class of direct thrombin inhibitors is hirudin. Bivalirudin is a synthetic analog of hirudin that binds reversibly to thrombin. It has been studied in a number of clinical trials.

Do you still “tan”? Why?: Melanoma (Part I)

Melanoma is a malignancy of melanocytes, cells derived from the neural crest that produce melanin pigment. The vast majority of melanomas originate in skin, but primary melanomas can also develop in any location populated by melanocytes, including any mucosal surface and the eye. In the United States, the incidence of cutaneous melanoma is fifth among all cancers in males and sixth in females. The incidence has been rising in the U.S. and European countries for at least the past 3-4 decades, in part attributed to increased sun (ultraviolet light) exposure.

Established and suspected risk factors for developing cutaneous melanoma include pale skin, red or blonde hair, past history of severe blistering sunburn, high sun exposure in early childhood, past use of skin tanning booths, multiple melanocytic nevi (moles), three or more dysplastic nevi and invasive cutaneous melanoma diagnosed in a first-degree relative. A family history of invasive cutaneous melanoma is present in approximately 5% of patients, and a small subset of these familial melanomas is associated with germline mutations in the CDKN2A (p16) gene.

The diagnosis of a primary cutaneous melanoma is suspected if a skin lesion demonstrates asymmetry, border irregularity, color variegation, diameter >6 mm, and evolution (change) over time.

Cutaneous Pigmented Melanoma

Amelanotic Melanoma

The vast majority of melanomas present as primary lesions without evidence of distant metastases; therefore, in most practice settings, the diagnosis is made by a dermatologist. Standard treatment for the primary lesion is wide surgical excision to achieve margins from the invasive component of 1 cm for lesions <1 mm in depth and 2 cm for lesions >1 mm.

The risk of regional nodal involvement by melanoma increases with the depth of the primary lesion. A sentinel lymph node biopsy (SLNB) can determine microscopic involvement of regional lymph nodes with high specificity and sensitivity, and patients with positive sentinel nodes have lower overall survival than those with negative nodes. Overall, approximately 15-20% of patients with a primary at least 1.0 mm deep will develop metastases to regional nodes. If a sentinel node is involved by melanoma, the risk of additional positive nodes in the regional node basin is approximately 12-20%. The current standard-of-care is to offer a completion lymph node dissection to patients with positive sentinel nodes.

In randomized trials, overall survival of patients undergoing elective lymph node dissection or SLNB +/- completion lymph node dissection is not improved, compared to patients who are observed after wide excision of the primary. In the latter patients, lymphadenectomy is offered only if regional nodes become clinically palpable. Despite the lack of clear evidence that SLNB improves overall survival, the procedure remains an important component of clinical practice because it provides prognostic information, and identifies higher risk patients for enrollment into adjuvant clinical trials. In addition, retrospective case series studies conducted to date do not exclude the possibility of a survival advantage for SLNB and completion lymphadenectomy in certain subsets of patients with intermediate thickness primary melanomas. A large multi-center randomized trial is currently ongoing to determine the benefit of the completion lymphadenectomy for patients with metastases in sentinel nodes.

Staging to assess prognosis for patients with cutaneous melanoma is based on the following major clinical and pathologic variables: depth (tumor thickness) of the lesion measured in mm (Breslow thickness); presence of epithelial ulceration in the primary as determined by histologic examination; presence or absence of regional node metastases; presence or absence of in-transit or satellite lesions (melanoma metastasis separate from the primary occurring between the primary and the regional draining nodes); microscopic versus macroscopic regional node metastases; and the presence or absence of distant hematogenous metastases.

Stage Grouping

For patients with stage IB melanoma, the risk of recurrence and death from melanoma at 10 years post-diagnosis exceeds 10%, and for patients with stage IIA disease, the risk of death over 10 years is in the range of 30%. Mortality for patients with deep ulcerated primaries (stage IIC) at 10 years can exceed 50%, and their overall survival is worse than patients with stage IIIA disease, demonstrating the important prognostic value of ulceration. Although most distant metastatic recurrences are detected within the first few years after diagnosis of the primary, metastatic melanoma may remain dormant for many years and may recur more than 20 years later. Patients are monitored for local or metastatic recurrence with physical exam, complete blood counts, liver function tests, serum LDH, and chest X-ray every 3-6 months, generally for five years. Although once or twice yearly PET-CT and/or body CT scans are also used to monitor for recurrence in high-risk patients, at this time the value of these procedures in improving overall outcome remains unclear.

Interferon-alfa is the only agent approved by regulatory authorities for adjuvant systemic treatment of melanoma after surgical removal of the primary and regional metastases. Randomized trials have shown that administration of interferon-alfa improves progression-free survival compared to observation alone in patients with primary melanomas greater than 4 mm deep or with regional node metastases. The effect of interferon on overall survival in these trials is less clear and remains a subject of intense discussion, although a meta-analysis of multiple trials suggests a small survival improvement for patients receiving interferon. Interferon administration can be associated with fatigue, fever, anorexia, depression, cognitive alterations, cytopenias and liver function test elevations. Currently, at least two adjuvant randomized studies are being conducted in stage III patients including a trial of the immune-modulating antibody ipilimumab (anti-CTLA4) and a separate study of a MAGE-A3 cancer vaccine. In both of these trials, patients in the control arm receive a placebo.

Hematogenous metastases of melanoma can be found in almost any organ or site. Melanoma has a particular predilection for metastases to brain; in autopsy series or during the course of the disease, brain lesions will be found in up to 50-75% of patients. Therefore, staging of the brain with contrast MRI, or if MRI is contraindicated, contrast CT, is included with the initial and subsequent staging of metastatic disease, even in the absence of neurologic symptoms. The management of brain metastases has been evolving over the past 10-15 years; many centers defer whole brain radiation and instead attempt to control the disease with surgery when clinically indicated and/or stereotactic or gamma-knife radiation.

When metastatic disease is initially detected, stage and prognosis are determined by the sites of metastatic disease and serum LDH. Patients with disease limited to skin and lymph node and normal LDH have the best overall survival. LDH above the upper limit of normal is a poor prognostic feature that overrides site of metastatic disease.

Current standard options for systemic treatment of metastatic melanoma are limited. They include single or multiple-agent chemotherapy, and high dose interleukin-2 (IL-2). The alkylating agent dacarbazine (DTIC) is the only chemotherapy drug approved for treatment of metastatic melanoma in the United States. It and its close relative temozolomide are associated with objective response rates that range from <10% to approximately 20%, and, generally, responses are short-lived. Chemotherapy has not been compared to supportive care only, therefore its effects on overall survival are not known. Other cytotoxic agents with low-level anti-tumor activity in metastatic melanoma include cisplatin, fotemustine (available in Europe) and the mitotic tubule toxins.

Interleukin-2, a cytokine with multiple immunologic effects, was approved for treatment of metastatic melanoma on the basis of composite data from multiple phase II trials.

Overall, the objective response rate to IL-2 is only 10-20% but approximately 5% of patients achieve durable complete regression of tumor.  Although IL-2 produces objective tumor response rates of 10-20%, durable tumor responses exceeding two years are only observed in approximately 5% of patients. All sites of disease are capable of responding, however minimal data are available for brain metastases because prior studies excluded active, untreated brain lesions.

IL-2 is given by 15-minute IV infusion every 8 hours for up to 14-15 doses in the hospital, in weeks 1 and 3 of an 8-12 week cycle. Treatment can cause severe adverse events including capillary leak syndrome and hypotension; low urine output; fluid retention; elevated creatinine; electrolyte abnormalities such as hypocalcemia, hypomagnesemia and hypophophatemia; myocarditis; elevated bilirubin and other liver function tests; fever, nausea, vomiting and diarrhea; skin rash; and confusion.

Strict eligibility criteria are used to select patients for IL-2 in order to minimize toxicity and optimize the risk-benefit ratio. The criteria include normal cardiac function, no evidence of ischemic cardiovascular disease as assessed by a cardiac stress test, adequate pulmonary function defined as FEV1 >2 liters and DLCO >70% of predicted, good major organ function, and no history of autoimmune disease.

Similar to other types of cancer, many combination regimens have been tested in patients with metastatic melanoma. High objective response rates, in some cases exceeding 40%, were reported from initial phase II trials of combination chemotherapy [e.g., the cisplatin-dacarbazine-vinblastine (CVD) regimen, or chemotherapy in combination with interleukin-2 and/or interferon-alfa (biochemotherapy)]. Subsequent multi-center randomized trials were unable to confirm the high response rates and to date none of the combination regimens has consistently produced improvements in overall survival. A median survival in the range of 8-9 months was observed for both control (DTIC and the CVD combination, respectively) and experimental study arms in two recent, negative, large randomized studies for patients with previously untreated metastatic melanoma. The only treatment shown to increase median survival in metastatic melanoma is ipilimumab.

Activating mutations in genes within tumors, particularly those that code for cell surface receptors and intracellular signaling molecules, can promote and sustain malignant behavior. Substantial clinical evidence is now available from other malignancies that small molecule drugs targeted to these ‘driver’ mutations can produce overall patient benefit. Mutations have also been discovered in melanoma tumors, several of which are likely to have immediate clinical relevance for the treatment of patients with metastatic disease.

Selected Genetic Alterations in Malignant Melanoma

The c-kit gene is mutated in 10-30% of acral-lentiginous and mucosal melanomas, and rarely in melanomas arising in chronic sun-damaged skin. Over the past four years, several reports, usually of a single patient or a small series, have documented the substantial anti-tumor activity of commercially available c-kit inhibitors (e.g., imatinib, dasatinib, nilotinib, sorafenib, sunitinib) when used to treat melanoma patients whose tumors harbor a c-kit mutation. The exact response rate is not known but the available data suggest that perhaps at least 80% will demonstrate tumor regression.

Responses are usually associated with marked reduction in tumor FDG [fludeoxyglucose (18F) or fluorodeoxyglucose (18F) which can be abbreviated 18F-FDG or FDG] uptake assessed by PET CT scan. The durability of the responses has also not been formally assessed, but preliminary data indicate that most patients will develop resistance to treatment over time or relapse within the central nervous system. Case reports demonstrate that some patients whose disease progresses on one c-kit inhibitor may respond to treatment with an alternate c-kit inhibitor.

Interpretation of the limited clinical data to date is complicated by several factors including the variety of mutations within the ckit gene, the availability of multiple c-kit inhibitors, and the varying sensitivity of the different mutations to inhibition by the different c-kit inhibitors. At this time, the activity of ckit inhibitors against tumors in which the c-kit gene is amplified but not mutated is not known. Preliminary data suggest that the c-kit inhibitors do not have activity in patients whose tumors have high-level expression of c-kit, as determined by immunohistochemistry, if the ckit gene is not mutated or amplified.

Activating mutations in the bRAF and the nRAS genes are found in approximately 40-60% and 15-25% of patients with primary cutaneous melanomas, respectively. The bRAF and nRAS mutations are mutually exclusive (not found in the same patient), and mutation in the bRAF gene is more commonly found in melanomas originating in intermittently sun-exposed skin. Initial phase II trials of sorafenib, a first-generation inhibitor of RAF proteins, produced very low rates of clinical response, thus casting doubt on the importance of the bRAF mutation as a potential therapeutic target.

Subsequently, two agents that are selective inhibitors of the mutant form of bRAF, plx4032 (RO518426) and GSK2118436, were advanced into clinical trials. Phase I trials of both agents, which included expansion cohorts of patients selected for bRAF mutations, demonstrated very high objective response rates exceeding 60% in metastatic melanoma patients whose tumors carry the mutant form of bRAF (at V600). Responses were not observed in tumors carrying the WT form of bRAF or mutant nRAS, and the sensitivity of tumors with mutations at other locations in the bRAF gene is currently unknown. For the PLX4032 agent, median duration of response has been in the range of 6-8 months. Overall, the agents have been well-tolerated, although a subset of patients has developed drug-related single or multiple keratoacanthomas or squamous cell cancers of the skin.

Other mutations and genetic alterations in melanoma may become important targets for therapy or biomarkers predictive of response to specific signaling pathway inhibitors. For example, a consistent activating mutation in the GNAQ gene was detected in 46% of uveal melanomas. Although specific inhibitors of GNAQ are not available, GNAQ activates the MAP kinase pathway, which can be inhibited by agents targeted to MEK. Several MEK inhibitors are currently in clinical trials and will likely be tested in patients with metastatic melanoma from ocular primaries.

Development of immune therapy approaches for treatment of melanoma proceeded in parallel to the substantial advances in understanding of tumor immunobiology over the past 25 years. Proof-of-concept for the value of immune therapy in melanoma was largely derived from the high dose interleukin-2 experience, in particular the low but consistent rate of durable complete responses produced by IL-2. Studies in animal models provided strong evidence that interleukin-2 activates T-lymphocytes capable of recognizing tumor specifically and mediating its destruction.

Substantial advances have subsequently been made in understanding the basis for T-cell recognition of antigens, and the molecular control of T-cell activation and function. In addition to defining signals that promote T-cell activation and proliferation, many of the signals, which regulate and modulate the evolving immune response within lymph nodes and the tumor microenvironment, have been discovered. These advances are the basis for previous and ongoing efforts to develop more effective anti-melanoma immunotherapy, including cancer vaccines; other immune-modulating cytokines; monoclonal antibodies to directly stimulate lymphocytes, or to block inhibitory signals received from other immune cells or tumor; and adoptive immunotherapy, which involves harvest, ex vivo expansion and reinfusion of patients’ own melanoma-specific lymphocytes.

T-lymphocyte immune responses against melanoma antigens can be found in many patients with melanoma. In addition, subsets of tumor cells are dividing and dying within existing lesions, suggesting that tumor antigens are constantly released and presented to the immune system. Several strategies can be taken to harness the ongoing tumor-host immune interactions in order to produce meaningful anti-tumor effects. Cancer vaccines attempt to direct the activation of the immune system very specifically against cancer (melanoma) antigens. To date, cancer vaccines as a sole strategy for treatment of melanoma have demonstrated limited activity.

A more direct but cumbersome approach requires the isolation, expansion and re-infusion of the patient’s own melanoma antigen-specific T-cells (adoptive immunotherapy). Recent studies show objective response rates of up to 50% and complete response rates of 15-20% for metastatic melanoma patients treated with combinations of lymphodepleting chemotherapy, followed by adoptive immunotherapy and concurrent administration of IL-2. Because of the difficulty in isolating and expanding melanoma specific T-cells in some patients, new approaches have been developed in which non-specific peripheral blood lymphocytes can be genetically engineered to recognize melanoma antigens.

A second approach to immune therapy involves relatively non-specific expansion of pre-existing patient T-cell responses against melanoma, by providing non-specific stimulatory signals, or removing inhibitory influences on T-cell activation and proliferation. Examples of agents in this class include IL-2 and anti-CTLA4. Autoimmunity against normal tissues is a potential toxicity of non-specific T-cell activation.

A third and promising approach to immune therapy of melanoma involves removal of immune inhibitory influences within the tumor microenvironment. Several mechanisms of immune suppression within the tumor microenvironment have been defined in animal models, and agents to block some of these immune suppressive factors are in clinical development.

Suggestive clinical proof-of-concept for the potential antitumor effects of this third approach to immunotherapy was recently provided by phase I trials of the monoclonal antibody, anti-PD1. When T-cells are activated, they bring the programmed death-1(PD-1) receptor to the cell surface. Binding of PD1 to its ligands causes downregulation of T-cell activity. One of the ligands for PD-1 (B7-H1, also called PD-L1) is expressed in melanoma, and highly expressed by a subset of melanomas derived from patients. Studies in animal tumor models show that tumor expression of B7-H1 is an important mechanism of self-defense against immune destruction.

Two phase I trials of a blocking antibody against PD1 have been conducted including a single dose study and a study of antibody administration every two weeks. The multi-dose trial examined the safety of 1, 3, and 10 mg/kg doses, and included expansion cohorts of metastatic melanoma at each dose level. A preliminary analysis of activity showed objective responses in 32% of 46 previously treated patients with metastatic melanoma. Although follow-up was less than one year in most patients, all of the responses were ongoing at the time of analysis. Similar to the experience with ipilimumab, mixed responses were observed, and tumor regression was preceded by progression in some patients. Anti-PD1 was tolerated well with a low frequency of autoimmune adverse events. Phase I trials of antibodies blocking PD-L1 are also ongoing, and multiple other mechanisms of immune evasion within the tumor microenvironment have been recognized and are potential future therapeutic targets.

Mature studies of ipilimumab (anti-CTLA4) and early data from trials of anti-PD1 suggest an important role for these and future immune modulating monoclonal antibodies in the treatment of melanoma. In addition to the small potential for acute hypersensitivity reactions common to most monoclonal antibodies, the major adverse events from immune modulating antibodies are likely to result from induced autoimmune reactions, or acute release of cytokines from activated immune cells. Management of toxicity in certain patients will paradoxically require the use of corticosteroids or other immune suppressants.

Unlike most small molecule drugs, the circulating half-life of antibodies is much longer and can be in the range of two to three weeks. Thus circulating levels of the antibody can persist for many weeks after the last dose of treatment, and similarly the biological effects can be maintained or perhaps appear weeks after treatment is stopped. Subclinical events from administration of one antibody may be exacerbated by administration of a new agent, for example, colitis may be enhanced or induced by subsequent administration of another immunotherapy such as IL-2 or theoretically by an agent that produces gastrointestinal toxicity. Thus caution is warranted when starting any new treatment following the administration of an immune modulating monoclonal antibody.

T-cell Activation

T cells become activated via a dynamic interplay with antigen presenting cells (APCs). APCs are specially equipped to display antigen with both major histocompatibility (MHC) class I and class II molecules for presentation to CD8+ and CD4+ T cells respectively. The MHC molecules display peptides to either CD8+ effector T cells (class I) or CD4+ helper T cells (class II). CD8 and CD4 are proteins on the surface of T cells, which help to define these subsets. The T cell receptor (TCR) is responsible for the exquisite specificity of this lock-key reaction to restrict recognition.

The binding of the TCR to an MHC molecule bound to an antigenic peptide is called signal 1. If this interaction happens in isolation, the T cell does not become activated and, in fact, can be anergized (functionally incapacitated) to the antigen. In order for activation to occur, the TCR-antigen signal must be accompanied by signal 2, represented by binding of the CD28 activation marker on the T cell to a co-stimulatory molecule (B7-1 or B7-2, aka CD80 and CD86) on the APC.

With signals 1 and 2 engaged, the T cell becomes activated and, a

Regulation of T-cell Activation is a complex process

mong other intracellular signals, begins to produce autocrine IL-2. At the same time that this activation is happening, a molecule known as CTLA-4 is transported through the T cell into the immunologic synapse where signals 1 and 2 are taking place. CTLA-4 plays a non-redundant role in dampening the now-activated T cell response by binding to the B7 molecules and thereby preventing them from ligating CD28. When CTLA-4 is engaged, it sets off an inhibitory program in the T cell which limits T cells proliferation and activation. The importance of CTLA-4 in preventing T cell hyper-activation is documented by the phenotype of CTLA-4 deficient mice, which die at 3-4 weeks of age after massive lymphoproliferation and infiltration of many organs with auto-reactive lymphocytes.

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Take a well-deserved break. I wish to write more but I am working tonight. I will update my post with more information tomorrow morning. Thanks for reading.

Chronic myelogenous leukemia

 

Here we go, let’s just say this is our case;

General Practitioner: I have a 54-year old patient who showed up for her annual, no complaints, feeling fine. But her routine blood work came back with a white count of 44,000, mild anemia and borderline thrombocytosis. She denied any infectious symptoms, and is not taking any steroids or other medications. I gave her a Zithromax prescription and told her to return in two weeks for a repeat CBC, and her WBC count is still high at 51,000. Should I refer her to you?

Hem/Onc MD: I’ve seen a lot of my patients present that way. I’d be surprised if it was an infection. Please have her call my office for an appointment right away. What does the WBC differential show?

GP: Fifty percent neutrophils, 15% monocytes, 4% basophils, and ‘myelocytes and metamyelocytes’ were also noted.

Hem/Onc MD: Any blasts?

GP: Two percent. What do you think?

Hem/Onc MD: Sounds like it’s probably a myeloproliferative disorder, quite possibly CML.

GP: You need me to send along all other annual tests we just did?

Hem/Onc MD:You can but it’s not necessary. We have to do a bone marrow biopsy and aspiration, and I will send the aspirate for flow cytometry and cytogenetics. If she has CML, we’ll be looking to find the ‘Philadelphia chromosome’ present in her metaphases.

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Chronic myelogenous leukemia (CML) is a clonal hematopoietic malignancy that is characterized by the overproduction of neutrophils in all stages of maturation secondary to a balanced translocation, t(9;22) (q34;q11.2), between the long arms of chromosomes 9 and 22, which is also known as the Philadelphia or Ph chromosome. The Philadelphia (Ph) chromosome is detected in approximately 95% of CML cases but is cryptic (i.e., not detectable by cytogenetic analysis but rather by the molecular rearrangement present) in all other patients with CML. This translocation creates a unique fusion gene, BCR-ABL, whose protein product, bcr-abl, is a constitutively-active tyrosine kinase that promotes unregulated granulocyte production and in some patients, unregulated platelet production. In the U.S. alone, approximately 4,500 new cases arise annually with a median age of onset of 53 years.

CML has been classified by the World Health Organization (WHO) as a chronic myeloproliferative disorder along with chronic neutrophilic leukemia, chronic eosinophilic leukemia (and the hypereosinophilic syndrome), polycythemia vera, chronic idiopathic myelofibrosis (with extramedullary hematopoiesis), essential thrombocytosis and other unclassifiable chronic myeloproliferative disorders (Table 1.1), because it involves a multipotent hematopoietic progenitor cell; overproduction of one or more of the formed elements of the blood; marrow hypercellularity and megakaryocytic dysplasia; extramedullary hematopoiesis; myelofibrosis and transformation to acute leukemia.

WHO Classification of the Chronic Myeloproliferative Disorders.

  • Chronic Myelogenous Leukemia (Ph chromosome, t(9;22)(934;q11) BCR/ABL positive
  • Chronic Neutrophilic Leukemia
  • Chronic Eosinophilic Leukemia (and the hypereosinophilic syndrome)
  • Polycythenia Vera
  • Chronic Idiopathic Myelofibrosis (with extramedullary hematopoiesis)
  • Essential Thrombocytosis
  • Chronic Myeloproliferative Disorder, unclassifiable

However, CML differs from many of the other chronic myeloproliferative disorders because, in contrast to most of them in the absence of effective therapy, its clinical course is usually measured in years rather than decades, terminal transformation to acute leukemia is inevitable and its timing is unpredictable; but most importantly, only CML is associated with the t(9;22) (q34;q11.2) translocation, for which there is now targeted therapy with the drugs imatinib mesylate and dasatinib.

Natural History

The natural history of CML has been phenotypically divided into three phases: chronic, accelerated and blastic. Eighty-five to 90% of CML cases in the U.S. are diagnosed in the early, or “chronic,” phase of CML. However, patients can present for the first time in any of the three phases, or can transform spontaneously from the chronic phase to blast crisis, even following remission induction. The blastic phase can be myeloid, lymphoid or undifferentiated. The chronic phase has also been divided into early and late stages and as the disease progresses there is an increasing tendency for the development of extramedullary hematopoiesis with enlargement of the liver and spleen; extension of the disease to the lymph nodes is usually a sign of transformation and is associated with the acquisition of additional chromosome abnormalities such as a reduplicated Ph chromosome.

Most descriptions of the natural history of CML derive from an era when medical care was less accessible, blood counts were not routine and the distinction between the various chronic myeloproliferative disorders was largely based on clinical phenotype and conventional cytogenetics. Furthermore, the impact of therapy, particularly with alkylating agents, was often not factored into descriptions of its natural history. Today, with greater access to medical care and the routine use of electronic cell counters, as well as more sensitive techniques for detecting mutations, patients are being identified earlier in the course of their disease and the phenotype of CML, as well as that of the other chronic myeloproliferative disorders, has changed.

Clinical Features

Given this increased access to medical care, it is not surprising that a substantial proportion of CML patients are now discovered incidentally during an evaluation for some other medical issue and that close to half are asymptomatic at the time of diagnosis. Fatigue, weight loss and night sweats are common symptoms and appear not to be related to disease stage, though, undoubtedly, in most cases the cause is hypermetabolism caused by the large turnover of myeloid cells. Fever and infection are uncommon. Interestingly, in one series, bleeding was a common feature, which appeared to be related to platelet dysfunction and thrombocytosis; however, in contrast to the other chronic myeloproliferative diseases, thrombosis is not a significant feature of CML. Rapid growth of the spleen can lead to early satiety and splenic infarction, which can be difficult to distinguish from a pulmonary embolism or pneumonia. Splenomegaly is present in over 75% of patients at the time of diagnosis and can be massive.

Laboratory Abnormalities

The hallmark of CML is the autonomous overproduction of myeloid progenitor cells such that the peripheral blood has the histological characteristics of the bone marrow with respect to the presence of circulating myeloblasts, promyelocytes, myelocytes, metamyelocytes, band forms and mature neutrophils that appear to be morphologically normal but lack the expected granules containing leukocyte alkaline phosphatase. The shift in immaturity is such that the number of myelocytes is frequently greater than the number of more mature myeloid cells. The platelet count can be normal or elevated to the extent found in essential thrombocytosis or polycythemia vera. By contrast, erythropoiesis is not increased and anemia is common but usually mild. An increase in circulating basophils is an important characteristic of CML and an increasing basophil count is a harbinger of disease acceleration.

Of course, exceptions to these phenotypic characteristics are well documented. For example, in some patients, thrombocytosis alone, often extreme, is the presenting manifestation of CML, and the characteristic basophilia and low leukocyte alkaline phosphatase score can be absent. In others, there is primarily a mature neutrophilic leukocytosis, making the disease difficult to distinguish phenotypically from the rare disorder, chronic neutrophilic leukemia. In a few patients, both neutrophilia and monocytosis are present, making the disease indistinguishable phenotypically from the myeloproliferative form of chronic myelomonocytic leukemia.

These phenotypic differences are frequently a consequence of the particular site of the breakpoint in the BCR gene. Thus, in most CML patients, the BCR-ABL fusion protein has a molecular mass of 210 kDa (p210) but in patients with a mature neutrophilic leukocytosis, bcr-abl is a 230 kDa protein (p230) and in patients with increased monocytes, BCR-ABL is a185 kDa protein (p190); p190 is also expressed in some patients presenting with acute lymphocytic leukemia.

Eosinophilia can also be a feature of CML and occasionally is sufficiently prominent to pose a problem in distinguishing these patients from those with hypereosinophilic syndrome, chronic eosinophilic leukemia or systemic mastocytosis. Although many of the latter patients respond to imatinib mesylate, the dose employed is lower and their natural history and complications are different.

A low neutrophil leukocyte alkaline phosphatase (LAP) score is a curious feature of CML but one that is not fixed, as the LAP score in CML can increase with infection, myelofibrosis, exposure to corticosteroids and during blast crisis. As mentioned, thrombocytosis, often extreme, can be the sole manifestation of CML and is the one situation in which neither leukocytosis nor a low LAP score may be present. In this situation, given the exquisite sensitivity of RT-PCR (reverse transcriptase-polymerase chain reaction) for BCR-ABL, to avoid false-positive results in the evaluation of a thrombocytosis patient for CML, other tests such as conventional cytogenetics or BCR-ABL fluorescence in situhybridization (FISH) technology should be employed instead for diagnosis.

The bone marrow aspirate in CML is hypercellular with a predominant myeloid hyperplasia with a left shift that will be characteristic of the particular phase of the disease. Thus, the blast cell count is less than 10% in the blood or bone marrow in the chronic phase, from 10% to 19% in the accelerated phase, and >20% in blast crisis. These thresholds represent the guidelines for a recently proposed WHO classification but other definitions exist, with somewhat different criteria (Table 1.2).

Criteria for Accelerated Phase according to MDACC, IBMTR and WHO.

MDACC IBMTR WHO
Blasts >15% >10% 10-19%*
Blasts + Pro’s >30% >20% NA
Basophils >20% >20%** >20%
Platelets <100 Unresponsive ↑, persistent ↓ <100 or >1000 unresponsive
Cytogenetics CE CE CE not at diagnosis
WBC NA Difficult to control, or doubling <5d NA
Anemia NA Unresponsive NA
Splenomegaly NA Increasing NA
Other NA Chloromas, myelofibrosis Megakaryocyte proliferation, fibrosis

NA = Not applicable, CE= Clonal evolution

* Blast phase >20% blasts (>30% for MDACC and IBMTR)

** Basophils + eosinophils

Like the other chronic myeloproliferative disorders, there is megakaryocyte hyperplasia in CML, but in striking contrast to the other disorders, the megakaryocytes are typically small and hypolobulated in CML. Because of the high leukocyte turnover, Gaucher-like cells stuffed with glycolipids may be seen. Myelofibrosis is rarely a presenting feature of CML but can develop with disease acceleration, as can red cell aplasia and lymphadenopathy. Bone infarction and hypercalcemia are usually features of blast crisis.

Given the phenotypic mimicry described above and the advent of targeted therapy, the diagnosis of CML requires the identification of the Ph chromosome or the BCR-ABL fusion gene in those patients in whom expression of the fusion gene is cryptic and conventional cytogenetics is not informative. In this instance, analyses for BCR-ABL by FISH or RT-PCR are diagnostically useful. Conventional cytogenetics has the advantage of identifying genetic abnormalities in other chromosomes besides the Philadelphia chromosome. These abnormalities may have adverse prognostic significance and include trisomy 8, isochromosome 17 and +19. From a therapeutic as well as a diagnostic perspective, a bone marrow aspiration and biopsy, together with conventional cytogenetics and quantitative RT-PCR for BCR-ABL in peripheral blood cells, are the preferred initial studies for CML.

The clinical features at the time of diagnosis have been incorporated into risk scores such as the Sokal and the Hasford. They take clinical features such as age, spleen size, percentage of blasts, basophils and eosinophils into a formula that defines patients with low, intermediate or high-risk disease. These classifications have been useful in defining the probability of progression.

Philadelphia Chromosome

  • The Philadelphia chromosome is detected only in the leukemic cells of CML patients and not in any other tissues including normal hematopoietic progenitors. The absence of the Philadelphia chromosome from normal hematopoietic progenitors enables the achievement of a complete cytogenetic response to medical therapy.
  • Polymerase chain reaction (PCR) technology can be used to detect BCR-ABL but, strictly speaking, not the Ph chromosome. Along with FISH, PCR can be useful for the diagnosis of CML in the absence of a Ph chromosome. In these cases, the BCR-ABL fusion is the result of a cryptic chromosome rearrangement. While a subset of normal healthy volunteers can be shown to harbor BCR-ABL, when sensitive methods of detection such as PCR are used, the Ph chromosome is never observed in healthy volunteers. Occasionally, cases of chronic neutrophilic leukemia are associated with a variant form of BCR-ABL. The reciprocal translocation, t(15;17), is associated with acute promyelocytic leukemia and results in the fusion of the PML and RAR genes.

CML Cytogenetics and FISH. Not the best picture but I'm not an artist. Where is Jess when you need her? :)

Pathogenesis of CML

In murine model systems, BCR-ABL is capable of causing a CML-like myeloproliferative syndrome. This phenotype is dependent upon the tyrosine kinase activity of BCR-ABL In human CML, the BCR-ABL-selective kinase inhibitor, imatinib mesylate, leads to a high response rate, which validates the importance of the tyrosine kinase activity of BCR-ABL in the pathogenesis of the disease. Preclinical studies suggest that SRC family kinases may play a role in CML disease progression to lymphoid blast phase. Although epigenetic changes in gene expression may play a role in the pathogenesis of CML, reversal of these changes does not appear to result in a significant percentage of remissions. There is no evidence that TNF-a activity plays a significant role in the pathogenesis of CML. While the normal ABL gene has a DNA binding domain that is retained in BCR-ABL, BCR-ABL does not localize to the nucleus and is not known to have appreciable DNA binding activity.

The molecular pathogenesis of CML has been the subject of intense scientific investigation. The Philadelphia (Ph) chromosome is a reciprocal translocation between chromosomes 9 and 22 that results in the formation of a fusion BCR-ABL gene, which encodes a protein tyrosine kinase with dysregulated enzymatic activity. The tyrosine kinase activity of BCR-ABL is essential to its ability to generate a CML-like state in lethally-irradiated mice transplanted with BCR-ABL-transduced stem cells. BCR sequences also play a vital role in facilitating oligomerization of BCR-ABL, which leads to activation via trans-phosphorylation.

At the molecular level, different BCR-ABL transcripts can be generated, depending upon the precise location of the BCR gene breakpoint. Most commonly, a 210-kd protein (P210) is formed. Occasionally, most often in cases of Philadelphia chromosome-associated acute lymphoblastic leukemia (ALL), a P190 is detected. Rarely, particularly in cases of chronic neutrophilic leukemia, a P230 isoform is created.

Because of differences in the chromosome 22 breakpoints, Ph+ ALL is frequently associated with a 190 kD protein (p190), whereas CML is most often associated with a 210 kD form (p210).

In vitro studies demonstrate that the p190 isoform of BCR-ABL harbors significantly more kinase activity than p210. This suggests some degree of negative regulation of the BCR-ABL p210 kinase by sequences in BCR that are absent in BCR-ABL p190. In addition to an increased level of ABL tyrosine activity as a result of the BCR-ABL fusion, BCR sequences contain sequences important for oligomerization, which are essential for the ability of BCR-ABL to induce cellular transformation in vitro.

Treatment:

A Case Study

A 47-year-old salesperson is diagnosed with chronic myeloid leukemia when a routine blood test revealed an elevated WBC of 74.3 x109/L with 4% basophils, 12% metamyelocytes, 6% myelocytes and 5% blasts. The platelet count was 563 x109/L and the hemoglobin 13.1 g/dL. The spleen was palpable 4 cm below the costal margin. The Sokal risk score is low. (To calculate Sokal risk score: http://www.roc.se/Sokal.asp)

***

The treatment of CML has changed significantly in recent years. For many years, hydroxyurea and busulfan were used as primary therapy. Although they effectively controlled peripheral blood counts in most patients, they rarely if ever produced cytogenetic responses. More recently, interferon alpha (IFN-α) became the standard therapy for most patients. The use of IFN-α resulted in cytogenetic responses in 40-50% of patients and they were complete in 5-20%. The addition of ara-C to IFN-α resulted in improved response rates, with some studies suggesting a survival advantage compared to IFN-α alone. Treatment with IFN-α, however, was associated with significant toxicity.

Imatinib, at a standard dose of 400 mg daily, has resulted in a complete cytogenetic response rate of 69% after 1 year of therapy and with five years of follow-up, 87% of patients have achieved this level of response at some time during imatinib therapy. A randomized trial (the International Randomized Study of Interferon and STI571 “IRIS” trial ), comparing imatinib to IFN-α + ara-C, demonstrated a significant advantage with imatinib in response rate, toxicity profile and progression-free survival. These responses have been largely durable. The estimated survival free of transformation to accelerated and blast phase CML at 5 years is 93% and the overall survival on an intent-to-treat analysis was 89% . Indeed, the rate of progression has decreased in the last 2 years of follow-up with <1% of patients losing their response or progressing in the 5th year of follow-up. Thus, imatinib has become the standard therapy for patients with CML.

The treatment of choice today for most patients with CML is imatinib and the standard dose is 400 mg daily. The role of hydroxyurea is merely to control the WBC for some time, for example, while determining if a patient has the Philadelphia chromosome or not. It should not be considered definitive therapy. The IRIS trial clearly documented the benefit of imatinib over the combination of interferon and ara-C in terms of response and tolerability. A survival advantage was not documented, probably because of the crossover design of the study, where patients not responding or tolerating their initial therapy were allowed to receive the alternative therapy. Because of this, over 90% of patients initially receiving IFN-α rapidly switched to receive imatinib. However, recent studies comparing imatinib to historical series of patients treated with interferon-based therapy have shown the expected survival advantage.

Several single-arm studies have suggested that higher doses of imatinib may be superior in terms of cytogenetic and molecular responses, and some have suggested a benefit in progression-free and transformation-free survival compared to historical controls. On-going randomized studies are trying to confirm the enhanced efficacy of higher doses of imatinib. Until these studies confirm an advantage, the standard dose remains 400 mg daily. There are no studies to show any advantage of imatinib in combination with interferon or any other agents. Although transplant has been used for many years, imatinib is considered today the best choice for most adults with CML. With a transplant-related mortality during the first year of at least 15% to 20% (and increasing with age) and the very favorable results with imatinib (survival rates of 92% at 5 years), almost all current patients should be considered for a trial with imatinib as first-line treatment.

For many years, interferon alpha was the standard therapy for patients with CML in the chronic phase who were not candidates for a stem cell transplant. The rate of complete cytogenetic response with interferon alpha varied in different studies (between 5% and 25%). Higher response rates were achieved with the combination of interferon alpha and cytarabine — up to 30% to 40%. Two randomized trials demonstrated this improved outcome with this combination that extended to progression-free survival, and improved survival was demonstrated in one of these trials.

Imatinib

It is important to educate the patient as to how to take imatinib. Although the initial studies were done with imatinib administered on an empty stomach, the current recommendation is to take it with a meal, preferably a light one. This has been shown to decrease the frequency of gastrointestinal adverse events, particularly nausea. While receiving imatinib, the patient should avoid acetaminophen because of the potential risk of liver toxicity. It is also recommended that grapefruit be avoided because of its potential interaction with the metabolism of imatinib. Other medications metabolized through the P450 can be administered but this should be done with caution. For example, patients who receive oral anticoagulants, (e.g., warfarin), should be closely monitored when imatinib is first administered and whenever a change in dose is introduced. For patients receiving a daily dose of 800 mg daily, splitting the dose into two equal doses of 400 mg is acceptable and may lead to improved tolerance.

Imatinib can be administered to the patient as soon as the diagnosis of CML is confirmed. It is not necessary to give other therapies prior to the start in an attempt to bring the WBC down.

Patients treated with imatinib should start therapy with the optimal dose at the outset of therapy. There is no evidence that a slow dose escalation improves, for example, tolerance. Indeed, it has been suggested that the use of suboptimal doses of imatinib may create conditions that increase the risk of developing resistance. In addition, there is growing evidence that the earlier the patient achieves a profound reduction in tumor load, the better their long-term outcome. Thus, the standard dose for patients receiving imatinib should be given at the start of therapy.

Allogeneic Bone Narrow Transplantation

Allogeneic bone marrow transplantation (BMT) can be curative in a significant proportion of CML patients eligible to receive this approach. Survival rates of 60-80% are frequently achieved in centers with experience. Besides availability of a donor and age, the major consideration is the risk of early mortality and long-term complications. Early mortality is usually lowest among younger patients, particularly those younger than age 20 to 30 years. The occurrence of late relapses, (more than 5 years after transplant), are increasingly being recognized and should also be taken into consideration. Extensive chronic graft-versus-host disease can be seen in as many as 60% of patients treated and other late complications may occur.

All of these issues need to be evaluated before opting for bone marrow transplantation. In addition, the experience level at the site where the transplant is to be performed needs to be considered. Reduced intensity conditioning regimens have expanded the population that may be eligible for transplant to include older patients, but the risk of relapse may be higher than with standard therapy. Transplant from alternative donors, (i.e., unrelated, cord blood), are also being evaluated but the potential for increased risks and lack of long-term data should be taken into account. Matched unrelated transplants may be associated with increased mortality and graft-versus-host disease, although molecular matching has decreased these risks considerably.

“Stem cell cures patients with CML”?

This has been the most common statement in the CML literature for many years and is still frequently seen today. Undoubtedly, stem cell transplant has cured many patients with CML. However, late relapses after transplant, (i.e., occurring more than 5 years after transplant), are increasingly being reported. The risk is small but constant and present as late as 20 years after transplant, (longer follow-up data is not available), complicating the definition of “cure” after transplant.

Furthermore, a subset of patients treated with interferon achieved undetectable transcript levels, (i.e., “complete molecular remission”), and none of these patients had relapsed after 10 years of follow-up. Studies following patients long-term after discontinuation of therapy with interferon have shown that approximately 50% had not relapsed. Thus, it is clear that some patients have been cured with interferon, although these represent a small subset of patients.

Stem cell transplant (SCT) is still a valuable treatment option for patients with CML. The best results are achieved in patients transplanted in the first chronic phase compared to those transplanted in the second chronic phase, (i.e., returning to the chronic phase after therapy for CML in the accelerated or blast phase). Results are also better for patients transplanted with cells from an HLA-identical sibling donor. Before the imatinib era, some reports initially suggested that prior therapy with interferon alpha adversely affected the outcome after stem cell transplant. However, multiple subsequent reports demonstrated this was not the case. Some of these subsequent reports suggested that suspending interferon at least 3 months prior to transplant could correct this alleged adverse influence. Studies reporting a similar analysis with prior exposure to imatinib have shown that prior exposure to imatinib does not adversely affect the outcome after SCT.

Frequently, after SCT, patients still have positive PCR for the first few months. However, only when these remain positive more than 6 months after transplant is there a correlation with a higher risk of relapse. Intervention for positive PCR during the first 6 months is usually not indicated.

Although the highest risk of relapse after transplant is in the first 2-3 years, it has become clear that late relapses do occur. There is a small but constant risk of relapse after 5 years, extending as far as 20 years after transplant. In addition, late complications of transplant include chronic graft-versus-host disease, osteoporosis, cataracts, secondary malignancies and infertility, although most patients who survive long-term after transplant have an adequate quality of life.

Cancer Treatment  = Complications

*** After 1 month of therapy, the white cell count has come down to 2.8 x109/L with 43% neutrophils and ANC [(absolute neutrophil count) 1.2 x109/L]. At this time, your recommendation should be to continue therapy unchanged and check CBC in 1 week.

The current recommendation for patients with CML in the chronic phase treated with imatinib regarding the management of myelosuppression is to hold therapy if the patient develops neutropenia or thrombocytopenia grade 3 or 4. Neutropenia is defined herein as an absolute neutrophil count of less than 1 x109/L. Some studies have actually used a lower threshold, (ANC 0.5 x109/L, which represents grade 4 neutropenia), as most patients recover rapidly and septic episodes are extremely uncommon. The treatment is reinstituted once the neutrophil count recovers above these levels. It is not necessary to discontinue therapy or to decrease the dose at absolute neutrophil counts higher than this level.

Although filgrastim has been shown to be of benefit in some patients with neutropenia, it is usually not recommended at the first occurrence of neutropenia, as this adverse event is relatively common during the first 2-3 months and because after a brief interruption of therapy most patients recover rapidly and do not experience this problem again. Filgrastim is best reserved for patients who experience prolonged or recurrent episodes of grade 3 or 4 neutropenia that compromise adequate dosing of imatinib. After treatment interruption for grade 3 neutropenia, treatment can be re-started at the same dose, provided the neutrophil counts recover within 2 weeks. If recovery takes longer than 2 weeks, dosage should be reduced to 300 mg if the patient was receiving therapy with 400 mg daily, (to 600 mg if the patient was receiving 800 mg daily and to 400 mg if previously receiving 600 mg).

One of the most common adverse events associated with imatinib therapy is myelosuppression. Myelosuppression is more common in patients who have failed prior IFN-α and is dose-related. Myelosuppression occurs most frequently during the first 2-3 months of therapy. After this time, few patients develop significant myelosuppression and most can continue therapy uninterrupted.

Overall, among patients treated with imatinib as first-line therapy, grade 3 or 4 neutropenia has been reported in 17%, thrombocytopenia in 9% and anemia in 4%. However, only 4% of patients develop neutropenia after 2 years of therapy, while 2% have thrombocytopenia and 2% become anemic. After 4 years of therapy <1% demonstrate any of these complications. It is very uncommon to have patients develop infectious or hemorrhagic complications associated with these events. In fact, in most instances myelosuppression is transient and self-limited and can be managed with short treatment interruptions. The use of hematopoietic growth factors, (filgrastim for neutropenia, oprelvekin for thrombocytopenia, erythropoietin or darbepoetin for anemia), has been reported to be effective in patients with recurrent or persistent cytopenias.

As with neutropenia, the recommendation for thrombocytopenia is to interrupt therapy for grade 3 or higher toxicity. Grade 3 thrombocytopenia is defined as a platelet count below 50 x109/L. The rules for re-instituting therapy are similar to those for neutropenia — if recovery above these levels occurs within 2 weeks, therapy is re-instituted at the same dose; if recovery takes longer than 2 weeks, a dose reduction, similar to the approach for neutropenia, is recommended.

Several studies have shown that the use of eythropoietic growth factors can result in improved hemoglobin levels in the majority of patients treated with imatinib who develop anemia. However, it should be emphasized that this is not an approved use of erythropoietin or darbepoetin at the moment. These agents are approved for use in patients with anemia associated with cancer therapy in non-myeloid malignancies.

*** A patient develops a rash that covers approximately 60% of the arms and the upper chest. There are a few small papules in the back and thighs. The rash is pruritic. The patient is taking 400 mg daily of imatinib. You continue therapy with imatinib at the same dose and treat the rash.

Occasionally, patients may develop skin rash while receiving therapy with imatinib. Prompt intervention is important to minimize treatment interruptions and to conserve dose intensity. Dermatologic treatment should be initiated at the first evidence of rash that may be related to imatinib. If the rash is grade 1 or 2, therapy with imatinib can continue but the rash should be treated. Patients may receive symptomatic therapy with antihistamines for the pruritis and topical and/or systemic steroids as needed. This controls the rash in most instances.

The patient described above has a grade 2 rash, because it is symptomatic, (thus not grade 1), and covers less than 50% of the total body surface, (thus not grade 3). If the rash does not respond to adequate management or progresses to grade 3, then imatinib therapy should be interrupted until it resolves to at least a grade 1. Therapy is then resumed at a lower dose: 300 mg daily if the patient was receiving therapy with 400 mg daily, 400 mg if the patient was receiving 600 mg daily and 600 mg if the patient was receiving 800 mg.

*** A patient with CML who is receiving therapy with imatinib 400 mg daily develops elevation of aspartate transaminase (AST) to 2-3 times the upper limit of normal. You continue therapy unchanged.

Proper monitoring and intervention to manage adverse events are important to optimize therapy in a way that preserves patient safety and offers the best possible outcome. In general, treatment interruptions are recommended when patients develop grade 3 or higher non-hematologic toxicity. For liver toxicity, this is defined as an elevation of transaminases to >5-20 times the upper limit of normal (ULN). Thus, the patient described above has grade 2 liver toxicity. Continuation of therapy unchanged is indicated in this instance. However, this should be accompanied by investigation of other potential causes of liver damage, (e.g., the concomitant use of other drugs that might cause liver damage), and close monitoring. The patient’s liver function tests should be monitored with increased frequency until the event is resolved or has stabilized.

If grade 2 toxicity persists, a temporary treatment interruption may be indicated and dose reduction considered. If the patient develops grade 3 liver toxicity, these measures should be instituted immediately with therapy restarted at a lower dose once the enzymes have returned to at least grade 1 level (i.e., <2.5 ULN). Sometimes patients require frequent interruptions because of liver toxicity. Although an occasional patient will eventually not show evidence of liver toxicity after multiple treatment interruptions, a patient with persistent and/or recurrent liver toxicity should discontinue therapy permanently and be offered alternative therapy with dasatinib.

Imatinib and Cardiac Failure

A recent report in the literature and, unfortunately, in the media suggested there might be an increased risk of cardiac toxicity and heart failure for patients receiving imatinib. Unfortunately, the reports about this possible adverse event misrepresented a very valuable study, mostly about potential cardiac effects of imatinib in animal models. In that study, a few (10) patients who had developed congestive heart failure while receiving therapy with imatinib were also presented. Although congestive heart failure has been described occasionally among patients with CML treated with imatinib, the incidence appears to be very low. In addition, when it has been reported, it is most frequently seen in older patients and in patients with pre-existing cardiovascular problems, (e.g., cardiomyopathy from interferon therapy, hypertension, coronary artery disease etc.), or risk factors for heart failure. (e.g., diabetes, prior use of cardiotoxic agents such as anthracyclines, etc.).

In the overall universe of patients treated with imatinib, the incidence of congestive heart failure does not appear to be any higher than would be expected in a population of individuals of similar age. Still, as for all other adverse events that may occur with imatinib, adequate monitoring and intervention are required. Imatinib may result in fluid retention and opportune therapy with diuretics when indicated is usually effective. For the occasional patient with symptoms that suggest congestive heart failure, an adequate work-up is indicated. Routine vigilance with echocardiograms, EKG or other similar cardiac tests is not indicated for the great majority of patients.

Treatment Failed?: Cytogenetic response

*** After 3 months of therapy with imatinib 400 mg daily, a patient with CML who started therapy in the chronic phase has achieved a complete hematologic response — a routine karyotype analysis in 20 metaphases shows 1 with the Philadelphia chromosome and 19 diploid.

Patients who have not achieved a complete cytogenetic response after 3 months of therapy still have over a 50% probability of achieving a complete cytogenetic response at 24 months with continuation of therapy. If no cytogenetic response is achieved by 6 months, the probability of achieving a complete cytogenetic response with continuation of therapy is approximately 15% compared to 50-80% if at least a minor cytogenetic response has been achieved. Therefore, no cytogenetic response after 6 months is considered as failure to imatinib.

By 12 months, patients with a partial cytogenetic response still have nearly a 50% probability of achieving a complete cytogenetic response with continuation of therapy compared to <20% for those with less than a partial cytogenetic response. However, earlier responses correlate with an improved long-term outcome. For example, patients who have not achieved a complete cytogenetic response after 12 months of therapy have a significantly lower probability of being alive and free from transformation or loss of response at 54 months (72%) compared to those with a complete cytogenetic remission (>90%).

This information has been incorporated into the current expert recommendations for the management of patients with CML. According to these guidelines, not achieving a complete cytogenetic response at 12 months from the start of therapy is considered a suboptimal response to therapy, whereas not achieving a complete cytogenetic response after 18 months of therapy is considered failure to therapy.

The standard definitions of cytogenetic response are based on routine cytogenetic analysis (karyotype) of at least 20 metaphases. A complete cytogenetic response is achieved when none of the 20 metaphases has the Philadelphia chromosome present following therapy. If the Philadelphia chromosome is present in 1-34% of metaphases, this constitutes a partial cytogenetic response. A minor cytogenetic response represents the presence of Ph in 35% to 95% metaphases. Some recent reports have subdivided minor responses into minor (35-65% positive) and minimal (>65% positive), although there does not appear to be any difference in the long-term outcome of patients between these two groups.

Based on the available data regarding the optimal responses that correlate with improved event-free survival, the definitions of failure to imatinib and suboptimal response have been established. These definitions take into consideration not only the response achieved but also the time at which responses are achieved.

Definitions for Failure and Suboptimal Response to Imatinib

Time Response
Failure Suboptimal
3 No HR No CHR
6 100% Ph+ >5% Ph+
12 >35% Ph+ >5% Ph+
18 >5% Ph+ No MMR (<3-log BCR-ABL/ABL)
Any Loss of CHR
Loss of CCgR
Mutation
CE
Loss of MMR
Mutation

HR: Hematological remission; CHR: Complete hematological remission; Ph+ve: Philadelphia chromosome positive; MMR: Major molecular response; CCgR: Complete cytogenetic response; CE: Clonal evolution.

*** A patient with CML in the chronic phase has been receiving imatinib at a dose of 400 mg daily with adequate tolerance. After 12 months of therapy, the patient has achieved only a partial cytogenetic remission, (i.e., 1-34% Ph+ metaphases).

In the patient presented, a partial cytogenetic response has been achieved at the 12-month mark, (a suboptimal response). This patient still has approximately an 80% probability of achieving a complete cytogenetic response with continuation of therapy and their probability of survival free from transformation is 93%. The response cannot be considered failure and consideration of stem cell transplant with the involved risks is not warranted; similarly, the response does not meet the current requirements for the use of dasatinib. However, it should be considered a suboptimal response, as a complete cytogenetic response is associated with a survival free from transformation at 5 years of 97%.

Increasing the dose to optimize response is recommended for all patients with suboptimal response to imatinib. All published data with dose escalation have been based on doubling the dose the patient is receiving. For example, this patient would receive 800 mg daily. Ongoing studies are evaluating the role of dasatinib and nilotinib in this setting, (suboptimal responses). Until these data are available, the standard in this situation should be dose escalation.

A complete cytogenetic response has been associated with improved survival. The presence of chromosomal abnormalities in other chromosomes in addition to the Philadelphia chromosome can be detected by a chromosome analysis (karyotype) and this phenomenon is associated with a worse outcome. Historical data from patients treated with interferon alpha have demonstrated that achieving a complete cytogenetic response correlates with an improved probability of survival. On a long-term follow-up, 78% of patients who achieved this response were alive after 10 years, compared to only 39% of those achieving a partial cytogenetic response and 25% of those with lesser responses.

There is usually a good correlation between the results obtained with cytogenetic analysis and FISH, although FISH has some false positivity. False positivity is low with the modern probes used, (usually at approximately 1-1.5%), but one has to be aware of the level of false positivity to be able to interpret positive results at low levels. However, molecular response is assessed by real-time PCR, which is 3-4 logs more sensitive than FISH and cytogenetic analysis.

Molecular remission

The definition for major molecular remission introduced in the IRIS trial is a 3-log reduction of transcript levels compared to a standardized baseline established in untreated patients. In this study, the ratio of BCR-ABL to BCR was assessed in a subset of patients prior to the start of therapy. The average of the results obtained from these patients was established as the baseline value from which patients would have to achieve a 3-log reduction to be considered major molecular remission. Patients who achieve a major molecular remission after 12 months of therapy have an improved probability of survival free of progression and survival free from transformation, compared to those without a major molecular response. A FISH analysis identifies cytogenetic response, not molecular response. PCR is at least 3-4 logs more sensitive than the standard FISH analysis.

Duration of Therapy

The current recommendation regarding duration of therapy with imatinib is to continue therapy indefinitely. There are a few small series of patients who have achieved a complete molecular remission, (sustained for more than 1 year), who stopped therapy with imatinib. Although in some patients no relapse had occurred at the time of the report, in most instances a relapse was seen, frequently as early as 3 months after the treatment was discontinued. Thus, for the moment, it is not recommended to stop therapy even after achieving a molecular response. Studies looking at strategies that may allow safe treatment interruption are being conducted.

Although PCR is a very sensitive technique for detection of the BCR-ABL chimeric gene, it still has a limit of detection. Even if PCR becomes negative, residual disease below the level of detection of the test might still be present. It is probably more appropriate to characterize this result as “undetectable transcript” rather than as “complete molecular remission.”

All done. All of a sudden imatinib doesn’t work anymore so you double the dose but still nothing.

Do we have any other options? Yes.

Imatinib at 400 mg/day is highly effective for the treatment of newly diagnosed chronic phase CML, achieving complete cytogenetic remissions in approximately 70% of patients after twelve months of therapy. Data from phase III studies reveal that survival without CML-related death in imatinib-treated patients exceeds 95% with five years of follow-up. Historically, the median survival of chronic phase CML patients was approximately 5-7 years. Imatinib is clearly providing a survival advantage in chronic phase CML patients.

Although complete cytogenetic remissions are common in CML patients treated with imatinib, the vast majority of patients have evidence of residual disease when sensitive methods of detection such as PCR are utilized. Additionally, most patients who are negative by PCR will develop detectable disease within 12 months of treatment interruption.

Although the progression of CML involves the accumulation of mutations that presumably cooperate with BCR-ABL to generate a true acute leukemia phenotype, initial response rates to targeted agents are, nonetheless, substantial. The durability of these responses is typically limited and, therefore, consolidative approaches such as allogeneic stem cell transplantation are recommended when available.

Although survival rates in imatinib-treated chronic phase patients are high with five years of follow-up, approximately 15% of patients have lost either an established hematologic or cytogenetic response, or have progressed to accelerated or blast phase. These patients are clearly in need of alternative therapies such as dasatinib.

Loss of response to imatinib is nearly always the result of loss of BCR-ABL inhibition. The best defined mechanisms are the acquisition of kinase domain mutations within BCR-ABL and overexpression of BCR-ABL through either genomic amplification or acquisition of additional Ph chromosomes.

Imatinib is metabolized in the liver by CYP3A4 and it is possible that CYP3A4 inducers may decrease exposure to imatinib but this has not been convincingly demonstrated in patients. SRC activation has been demonstrated in a small number of cell lines that were established from imatinib-resistant patients but its contribution to clinical imatinib resistance remains to be defined. Interestingly, mutations in two other imatinib targets, KIT and PDGFR, have been detected in cases of disease states, (e.g., GIST and hypereosinophilic syndrome), driven by these genes that have lost response to imatinib. However, studies of imatinib-resistant CML have failed to identify resistant mutations in kinases other than BCR-ABL. Of note, cases of non-small lung cancer that have lost an established response to gefitinib or erlotinib are most frequently associated with the acquisition of kinase domain mutations in EGFR.

Molecular Mechanisms of Acquired Imatinib Resistance

Although a trial of dasatinib or nilotinib is likely to be effective for patients who have lost a response to imatinib, it is important to determine if patients harbor the T315I mutation, which fails to respond to these agents. If so, proceeding directly to BMT or pursuing third generation kinase inhibitor therapy, (e.g., agents designed to specifically target the T315I), in a clinical trial setting are indicated.

Although dasatinib is a potent SRC inhibitor, nilotinib does not inhibit SRC family kinases. Both drugs appear to be efficacious for the treatment of imatinib-resistant CML. The activity of the drugs against nearly all imatinib-resistant mutations in vitro is responsible for their clinical utility in imatinib-resistant CML. Their increased potency is valuable in cases of imatinib resistance driven by overexpression of BCR-ABL and may lead to deeper remissions in imatinib-naïve cases. Both dasatinib and nilotinib will be compared with imatinib in newly diagnosed cases of CML in large clinical trials.

While both dasatinib and nilotinib have activity against most imatinib-resistant mutations in vitro, one imatinib-resistant mutation, BCR-ABL/T315I, is highly resistant to both these agents and is likely to be responsible for most cases of loss of response to these agents. Also, it is likely that a small number of additional mutations will contribute to resistance to these agents. To date, no responses have been observed in any patient who harbored this mutation prior to therapy with either dasatinib or nilotinib. It is, therefore, reasonable to exclude such patients from being treated with these agents.

Beyond kinase domain mutations, it is expected that a small number of cases will be associated with activation of alternative growth promoting pathways. Although BCR-ABL overexpression may be encountered in cases that develop resistance to second generation agents, the increased potency of dasatinib and nilotinib will likely minimize the contribution of this mechanism of loss of response to imatinib in cases treated with these inhibitors.

*** A patient has been receiving imatinib for 3 years. He achieved a complete cytogenetic remission after 12 months of therapy but has never achieved a major molecular remission. He has been receiving therapy with imatinib 400 mg daily. On his routine 3-month follow-up, he is found to have 16/20 (80%) metaphases Philadelphia chromosome positive. His peripheral blood is still compatible with complete hematologic remission and there is no splenomegaly. He has been tolerating imatinib well. A mutation analysis shows a mutation E255K (P-loop mutation). The patient has no sibling donors. Now what?

The loss of a complete cytogenetic remission while on adequate therapy with imatinib is considered failure to therapy by current guidelines. Five-year follow-up of patients with chronic phase CML who received imatinib as front-line medical therapy suggests that approximately 17% of patients have either lost an established response, (hematologic or cytogenetic), or have progressed to accelerated or blast phase. Additionally, nearly 10% of patients never achieve a major cytogenetic response and approximately 2-5% of patients are unable to tolerate therapeutic doses of imatinib (>300 mg daily).

The best results with interferon are achieved when it is used in the first year after the diagnosis of CML; after that, the rate of major cytogenetic response drops significantly to less than 10% probability. There is only anecdotal experience with the addition of interferon alpha to imatinib after the patient fails imatinib — the results have not shown any significant benefit and tolerance has not been good. Discontinuing imatinib and starting interferon alpha have resulted in no benefit and toxicity is high. Thus, using interferon, whether alone or in combination with imatinib, would not be an adequate choice. Hydroxyurea can only control the WBC but has no benefit in terms of cytogenetic response, which is what this patient needs. A stem cell transplant can be considered in this patient but, in the absence of a sibling donor, the risk increases. It may be adequate to start a search for a donor in the bone marrow registry.

However, with the recent introduction of the new generation of tyrosine kinase inhibitors, these targeted therapies have become the treatment of choice for most patients. Dasatinib has induced major cytogenetic responses in 51% of patients (complete in 40%). Response rates are nearly identical whether a mutation is present or not. According to the available follow-up data, responses appear durable, with approximately 90% sustained for more than 1 year. Similar responses have been reported with nilotinib, although this agent is currently not yet FDA approved. Increasing the dose of imatinib has been used and before the introduction of dasatinib this would have been the treatment of choice. However, a randomized trial that compared an increased dose of imatinib (800 mg) to starting dasatinib in patients who failed imatinib at doses of 400 to 600 mg daily showed a significantly higher response rate and improved time to progression with dasatinib.

  • Dasatinib has been approved by the U.S. F.D.A. for imatinib-resistant and imatinib-intolerant CML, as well as for Philadelphia chromosome-positive ALL cases that are resistant to or intolerant of prior therapy. After five years of imatinib therapy, approximately 20-30% of chronic phase CML patients are eligible for dasatinib therapy. Studies to evaluate the efficacy of dasatinib in newly diagnosed CML patients are ongoing. Although dasatinib harbors activity against the KIT tyrosine kinase, it is not presently indicated in imatinib-resistant cases of GIST.

Doses below 300 mg daily are generally considered suboptimal. For example, in the original phase I study of imatinib after interferon failure, patients treated at doses below 300 mg had a significantly lower response rate compared to those treated at doses of 300 mg or higher,(hematologic response 53% vs. 98%, cytogenetic response 11% vs. 54%, respectively).

Patients with >35% Ph+ metaphases after 6 months of therapy are considered to have a suboptimal response and dose escalation is usually recommended. Some patients are not be able to tolerate dose escalation. Continuing imatinib therapy, even at the same dose, with sustained corticosteroid therapy can be risky. It is better, therefore, to switch these patients to dasatinib. The current studies of new generation tyrosine kinase inhibitors (nilotinib, dasatinib) show very little cross-toxicity. Thus, it is unlikely that these patients will develop skin toxicity with dasatinib and a more sustained therapy could lead to an improved response.

Although side effects are observed with dasatinib, patients who were unable to tolerate imatinib because of grade 3 or 4 non-hematologic toxicity generally did not have recurrent toxicity on dasatinib. Although both drugs can cause bothersome side effects, there does not appear to be significant overlap of symptoms in patients who have been treated with both agents.

Although these agents are still young and little data exist in this regard, a recent publication has suggested that approximately 50% of patients who have failed imatinib and nilotinib can respond to dasatinib, although not always with a cytogenetic response. Preliminary observations with nilotinib suggest that the opposite may also be true in some patients, (i.e., response to nilotinib after failure to imatinib and dasatinib). This is obviously very important because it offers the patient the possibility of effective second- and third-line therapies.

Dasatinib is generally very well tolerated but some adverse events can be observed. Fortunately, most of these are mild and can be managed with timely intervention. Headache has been reported in approximately 30% of the patients. However, headache is rarely severe and very seldom requires treatment interruptions or dose reductions. It responds to analgesic therapy and frequently disappears spontaneously despite continuation of therapy.

Myelosuppression can occur in patients treated with dasatinib. Grade 3-4 neutropenia or thrombocytopenia can be seen in up to 45% of patients treated in the chronic phase. The incidence may be higher in patients treated in the advanced stages of the disease but in these instances it is frequently difficult to differentiate from the cytopenias that are characteristic of the disease itself. The myelosuppression is most frequently transient and does not always require dose reductions.

Pleural effusions can be seen in a small subset of patients treated with dasatinib. Among patients treated in the chronic phase, the incidence has been reported at 17%, but only 3% are grade 3 or 4. Early identification is important as many patients will respond to treatment with diuretics and/or a short course of systemic corticosteroids. Pleural effusion is more common in the more advanced stages of the disease, reaching approximately 30% in the blast phase, but it is usually grade 1 or 2. Overall, only 8% of patients with CML in the chronic phase treated with dasatinib have been reported to have discontinued therapy because of adverse events.

Dasatinib has substantially greater potency against BCR-ABL than imatinib. BCR-ABL-positive hematopoiesis is typically dramatically inhibited, which can lead to cytopenias in a substantial proportion of patients. Therefore, careful monitoring of blood counts is indicated. Cytopenias should be managed with growth factors and transfusions as indicated.

If the patient harbors a substantial number of BCR-ABL-negative hematopoietic progenitors, cytopenias typically resolve and the patient is unlikely to develop recurrent cytopenias. Because no grade 3 or 4 cytopenias have been observed when therapeutic doses of dasatinib have been administered to solid tumor patients, it is not likely that the drug is inherently myelosuppressive.

***

Accelerated Phase of CML

The accelerated phase of CML is defined by WHO as the presence in the or marrow of 10-19% blast cells and 20% or more blood basophils, persistent thrombocytopenia (<100,000/μL) unrelated to therapy blood or thrombocytosis (>1,000,000/μL) unresponsive to therapy, together with increasing splenomegaly and leukocytosis unresponsive to therapy and cytogenetic evidence of clonal evolution. Other definitions specify a blast cell count of 15-29% in the blood or marrow; greater than 30% blast cells plus promyelocytes together in the blood; or bone marrow with blast cells less than 30%.

*** For the past two days, the patient has become progressively short of breath with a nonproductive cough and chest pain on exertion. On physical examination, he is acutely dyspneic and diaphoretic. The pulse is 110 per minute and the blood pressure is 140/80. Funduscopic examination reveals scattered retinal hemorrhages. There is jugular venous distention and breathing is labored. There is bilateral axillary adenopathy. The chest is clear to percussion and auscultation but there is sternal tenderness. Cardiac examination reveals a soft systolic murmur and an accentuated pulmonary second sound. Abdominal examination reveals hepatosplenomegaly with tenderness laterally over the spleen but no rub is heard. Examination of the extremities reveals pretibial edema and scattered ecchymoses. An ECG shows sinus tachycardia and right axis deviation and a chest x-ray demonstrates increased interstitial markings. On a chest spiral CT, there are thickened interlobar septa with patchy areas of ground glass opacity without focal consolidation. An arterial blood gas reveals a pO2 of 55 mm Hg on room air. The uric acid is 9 mg %, the serum creatinine is 1.2 mg % and the electrolyte panel is normal except for a mild respiratory alkalosis.

This is called Pulmonary hypertension secondary to pulmonary leukostasis.

The clinical picture is most compatible with pulmonary leukostasis in a patient with an elevated leukocyte count and an increased proportion of blast cells. Exertional angina and fluid retention are concomitants of pulmonary hypertension that can occur without the presence of coronary artery disease. Dyspnea in this situation is a consequence of hypoxia. The spiral CT makes it unlikely that a pulmonary embolism is the cause of the right heart strain. Tumor lysis syndrome is characteristically seen following chemotherapy-induced tumor reduction. It is manifested by hyperphosphatemia, hypocalcemia, hyperkalemia, hyperuricemia (>10 mg %) and renal failure.

The apparent failure of the supplemental oxygen therapy is a test-tube artifact resulting from increased oxygen consumption by the high number of leukocytes. Although pulse oximetry is subject to technical inaccuracy, in this instance it would be a useful measure of in vivo blood oxygenation. The apparent hypoglycemia also occurs because of the consumption of glucose by the large number of leukocytes in the blood sample and requires no therapy. Ice alone is often not sufficient to prevent consumption of oxygen or glucose in a blood sample containing a large mass of leukocytes, and the addition of a metabolic inhibitor such as sodium azide is usually necessary for this purpose.

Treatment for Pulmonary hypertension secondary to pulmonary leukostasis

Although there is not extensive experience, imatinib has proved effective in treating pulmonary leukostasis. Hydroxyurea at doses of 3-4 g per day has also been used to treat pulmonary leukostasis but this patient developed disease progression on the drug and its beneficial effects in this regard would at best be temporary. Leukapheresis, if available, can be an effective means of lowering the leukocyte count temporarily and should be considered, particularly if there are neurologic signs or increasing pulmonary compromise. Cyclophosphamide can rapidly lower the leukocyte count but in this instance, imatinib, because of its target cell specificity, would be the drug of choice. Anemia is actually a protective mechanism when there is hyperleukocytosis and leukostasis, since it contributes to reducing whole blood viscosity. As blood viscosity is an exponential function of the hematocrit, red cell transfusion is contraindicated until the leukocytosis has been controlled.

A bone marrow aspirate and biopsy, and cytogenetics are obtained. The marrow is hypercellular with the expected left-shifted myeloid hyperplasia, including 20% blast cells. Micromegakaryocytes, pseudo-Gaucher cells are seen, stainable iron is present and reticulin is increased. However, there is a paucity of red cell precursors. The paucity of red cell precursors suggests the presence of red cell aplasia.Although the marrow histology is compatible with the accelerated phase of CML with respect to the myeloid criteria, the marked decrease in red cell precursors is not typical. Together with the very low reticulocyte count, the paucity of red cell precursors suggests that the patient is developing red cell aplasia. In this setting, red cell aplasia can be a harbinger of transformation. Overproduction of hematopoietic progenitor cells in a specific lineage-restricted pathway is not a cause of decreased production in other hematopoietic lineage-restricted pathways.

*** A 73-year-old man with type 2 diabetes mellitus is referred for evaluation of leukocytosis; a leukocyte count one year previously had been normal. Other than diabetes, which had required laser therapy for retinopathy and a complaint of fatigue, the patient had no other medical problems. Physical examination reveals a blood pressure of 140/95 mm Hg, a few retinal microaneurysms and a palpable spleen tip. Laboratory studies reveal a hemoglobin of 11.0 g %, an MCV of 98 fL, a leukocyte count of 76,400/μL with 12% myelocytes, 2% metamyelocytes, 18% bands, 56% neutrophils, 2% monocytes and 10% lymphocytes, and a platelet count of 366,000/μL. The bone marrow aspirate and biopsy are histologically compatible with chronic phase CML and a cytogenetics study reveals the Ph chromosome translocation as well as a del9. You start imatinib at a dose of 400 mg daily with 300 mg of allopurinol.

There is no evidence that the magnitude of the leukocyte count influences the effectiveness of imatinib and studies of the efficacy of higher doses of imatinib, as compared to the 400 mg dose, are still incomplete. The current standard of care in CML in the chronic phase is 400 mg of imatinib daily with 300 mg of allopurinol for hyperuricemia, (or to prevent it when the leukocyte count is elevated). Leukocyte count reduction with imatinib is sufficiently rapid that adjunctive therapy with hydroxyurea is unnecessary. The combination of hydroxyurea and imatinib could lead to significant neutropenia, resulting in the need to interrupt treatment or add growth factor support.

*** With treatment, the patient’s leukocyte count is reduced to normal and the platelet count is unchanged, but the hemoglobin level remains at 11.0 g % and the patient still complains of easy fatigability. A recent colonoscopy was normal and three stool specimens tested negative for occult blood. The reticulocyte count is 0.9%, the MCV 89, the serum creatinine is 1.0 mg %, a blood smear shows no abnormalities and a urinalysis is normal. Anemia? Why? Because the erythropoietin deficiency is secondary to underlying diabetes mellitus.

Anemia is a consequence of untreated CML and can also be a consequence of imatinib therapy but this patient’s leukocyte count has been brought under control and the platelet count remains normal, suggesting that neither CML nor imitanib is causing bone marrow suppression. Diabetes mellitus is a significant cause of anemia as a result of diminished erythropoietin production even in the absence of chemical evidence of renal impairment. Correction of anemia with erythropoietin therapy is indicated because the patient is symptomatic.

*** The patient’s hematologic response is excellent once his anemia has been corrected but now, a month later, he complains of periorbital edema and a severe headache. A CT scan shows cerebral edema.

Stop the imatinib! Imatinib is known to cause fluid retention manifest often as periorbital edema and weight gain and rarely as cerebral edema. Diuretics have not been effective in imatinib-induced cerebral edema. The imatinib must be stopped because imatinib-induced cerebral edema has been fatal. Retreatment with imatinib has also been associated with recurrence of the cerebral edema.

Lowering the dose of imatinib for minor degrees of toxicity (Grade 1-2) is unacceptable since this increases the possibility of losing the response and permitting the emergence of imatinib-resistant clones. For higher degrees of toxicity, stopping imatinib is mandatory until satisfactory resolution of the toxicity. Restarting at a lower dose may be necessary but not lower than 300 mg qd.

***A 46-year-old man with chronic phase CML complains of fatigue, anorexia and numbness and tingling of his fingers and toes. The patient has been taking interferon. The hematocrit is 33%, the MCV 110, the leukocyte count 25,000/μL. The platelet count is 100,000/μL and the reticulocyte count 0.05%. A red cell folate level is 200 nmol/mL. The serum vitamin B12 level is 545 pmol/mL. This is Pernicious anemia.

Myelodysplasia is usually a complication of CML treated with imatinib but neurologic symptoms are not a feature of myelodysplasia. In CML, there is an increase in the circulating level of transcobalamin I, a vitamin B12 carrier that does not deliver the vitamin to the tissues. Transcobalamin I can compete for available vitamin B12 with transcobalamin II, the physiologic carrier of vitamin B12, which is present in the circulation at a much lower concentration. Therefore, it is possible to have megaloblastic anemia from B12 deficiency without a decrease in the total serum B12 level. Folic acid is dependent on vitamin B12 for both its entry into the red cell and its storage there. When the level of available vitamin B12 that is carried on transcobalamin II is low, red cell folate will be low as well. Rarely, interferon therapy can cause a neuropathy but it would not cause macrocytosis.

*** A 40-year-old woman is referred for excessive bleeding following a tooth extraction. The patient claims general good health but does note that over the past year she has bruised easily and that her menses have become excessive, which she considers premenopausal. Physical examination is normal except for some scattered ecchymoses on the extremities. The blood counts reveal a hemoglobin of 11.0 g %, an MCV of 85 fL, a leukocyte count of 11,000/μL with 75% neutrophils, 5% monocytes, 18% lymphocytes, 2% basophils and a platelet count of 2,750,000/μL. Hmm? How about a ristocetin cofactor activity assay now? Now? What about NOW?

The patient’s hemorrhagic diathesis is manifested by surface hemorrhage and thus would not likely be caused by an abnormality of the extrinsic pathway. While acquired factor V deficiency has been documented in CML, this has usually been associated with very high leukocyte counts. The bleeding time can be normal or elevated with thrombocytosis and does not define the mechanism for hemorrhage. Essential thrombocytosis (ET) could well explain the patient’s clinical phenotype. However, the presence of basophilia would be distinctly unusual in ET and the JAK2 V617F mutation is present in only 45% of ET patients, making it a relatively insensitive test.

The patient’s hemorrhagic diathesis and the quality of the bleeding suggest a platelet or vascular defect, or von Willebrand’s disease. Given the recent onset of bruising and bleeding, the defect is likely to be an acquired one and given the marked thrombocytosis, it is most likely an acquired form of von Willebrand’s disease. With marked elevation of the platelet count, there is increased destruction of the largest and most hemostatically effective von Willebrand multimers, causing a type 2 form of von Willebrand’s disease. This is best identified by a ristocetin cofactor assay and values less than 30% are usually associated with an hemorrhagic diathesis. CML can present as isolated thrombocytosis but RT-PCR for BCR-ABL should not be used as the diagnostic test for CML because the test is not sensitive and false-positive results have been obtained in patients with essential thrombocytosis.

There is no correlation between the magnitude of the platelet count and major vessel thrombosis. In CML, in contrast to the other chronic myeloproliferative disorders, major vessel thrombosis has not been a significant complication associated with thrombocytosis. CML patients, however, are still at risk for the transient microvascular complication of thrombocytosis such as ocular migraine, erythromelalgia or transient ischemic attacks.

There is a direct correlation between the magnitude of the platelet count and the risk of bleeding because as the platelet count exceeds 1,000,000/μL, high molecular weight von Willebrand multimers are adsorbed and destroyed by the platelets, leading to an acquired form of von Willebrand’s disease. Since there is no correlation between the platelet count and thrombosis, reducing the platelet count, without reference to other possible risk factors for thrombosis, will not reduce the risk of arterial thrombosis.

*** A bone marrow aspirate and biopsy are performed on the patient for diagnostic purposes. The patient calls the next morning complaining of continual oozing of blood from the biopsy site, which has soaked her night gown. On physical examination, there is a large superficial ecchymosis at the biopsy site tracking down the right thigh and there is continuous oozing of blood from the biopsy puncture site. You give her epsilon aminocaproic acid.

The bleeding is not from lack of vitamin K-dependent clotting factors and an infusion of fresh frozen plasma would only expose the patient to allogeneic plasma. Activated factor VII is generally reserved for deep-seated hemorrhage secondary to a circulating inhibitor of coagulation or a deficiency of vitamin K-dependent factors such as occurs with a coumadin overdose and requires very prompt correction. Given the magnitude of the patient’s platelet count and the mechanism for the hemorrhagic diathesis, a platelet transfusion would either have no effect or would actually aggravate the problem.

Epsilon aminocaproic acid is an antifibrinolytic agent that stabilizes the platelet plug and is an effective hemostatic agent in von Willebrand’s disease when given either orally or intravenously. Alternatively, an infusion of DDAVP, which releases high molecular weight von Willebrand multimers from endothelial cells, could be tried. Both of these approaches would only be temporary. Plateletpheresis is an inefficient, temporary procedure, which often does not reduce the platelet count to the desired level and is subject to rapid rebound of the platelet count.

In the absence of other electrolyte abnormalities, the most likely cause for the hyperkalemia is potassium release during clotting of the blood sample as a result of the great mass of platelets in the sample. An ECG would not show tall, peaked T waves or a shortened QT interval but is probably unnecessary at this potassium concentration in an asymptomatic patient without evidence of cardiac, renal or endocrine disease. Since the most likely cause of the hyperkalemia is a test-tube artifact secondary to platelet potassium release upon blood coagulation, no therapy is necessary. A repeat serum potassium alone would only confirm the initial results.

A repeat serum potassium on a sample of anticoagulated blood will be normal, confirming the basis for the test-tube artifact.

*** A 44-year-old physician is noted to have a mild anemia and leukocytosis on a routine health maintenance evaluation. The patient has been asymptomatic and without prior medical problems. A year previously, his hemoglobin was 14.0 g %, the leukocyte count 3,700/μL with 74% neutrophils, 20.5% lymphocytes, 5% monocytes and 0.5% basophils, and the platelet count 194,000/μL. Physical examination is normal. Laboratory studies reveal a hemoglobin of 12.3 g %, an MCV of 88 fL, a leukocyte count of 21,140/μL with 49% neutrophils, 7% bands, 7% metamyelocytes, 16% myelocytes, 4% promyelocytes, 1% myeloblasts, 2% basophils, 8% monocytes and 6% lymphocytes, and a platelet count of 224,000/μL.

Although cytogenetic analysis is essential for monitoring therapy in CML, marrow cytogenetics is the important focus of this type of analysis and the lack of sufficient dividing cells may render peripheral blood cytogenetics less sensitive. Conventional cytogenetics also permits identification of other cytogenetic abnormalities that may be present such as trisomy 8 or isochromosome 17q. Peripheral blood BCR-ABL FISH, which assesses interphase nuclei, avoids the difficulties associated with a lack of dividing cells in the peripheral blood, but there is not the same record of experience with it as there is with conventional cytogenetics with respect to the effects of chemotherapy, and its degree of sensitivity is not that much greater. FISH analysis is useful when the Ph translocation is not detected by conventional cytogenetics and before therapy for identifying complex or variant translocations other than t(9:22)(q34;q11), Ph amplification and del9.

Real time quantitative RT-PCR for bcr-abl in the peripheral blood should be done before therapy to provide a baseline for monitoring residual disease during therapy. A bone marrow aspirate, biopsy and conventional cytogenetics should be performed for diagnostic purposes, and to provide a baseline for monitoring the effects of chemotherapy. Leukocyte alkaline phosphatase (LAP) is usually low in CML in contrast to polycythemia vera. However, the LAP score can be affected by disease status (increased in blast crisis), corticosteroid use, myelofibrosis and infections and may not be not depressed in CML presenting with isolated thrombocytosis.

Some ethics

A physician should discuss every aspect of the disease and treatment with the patients and their relatives. Disease stage and cytogenetic abnormalities are important prognostic factors, these all have to be discussed and explained. Early chronic phase without additional cytogenetic abnormalities offers the best prognosis, although there is still a small but finite risk of rapid conversion to blast crisis. Age, spleen size, platelet count and % peripheral blood myeloblasts have also been shown to predict the cytogenetic response to imatinib.

Allogeneic bone marrow transplantation is the only known curative therapy for CML. Let’s just say the patient has a healthy sister, who, if willing, should be tissue typed. A relative risk score for bone marrow transplantation has also been devised to aid in decision-making with respect to this procedure. Since the long-term effectiveness of imatinib has not yet been established and bone marrow transplantation has a finite immediate mortality risk and the possibility of substantial morbidity, patients preference become a vital piece of the therapeutic equation.

In 1984, Sokal and his colleagues analyzed the clinical features of 813 chronic phase CML patients to determine the prognostic significance of these features. Four clinical variables — age, spleen size, platelet count (>700,000/mL) and percent circulating blast cells — were found to segregate patients into low, intermediate and high risk groups with respect to their responsiveness to conventional chemotherapy therapy. However, the same risk factors appear to be useful for more modern forms of therapy such as interferon alpha and imatinib.

A common question is that weight matters. No. Clinical trial data has indicated that 400 mg per day is the effective imatinib starting dose for chronic phase CML. There is no need to adjust the starting dose of imatinib on a weight basis. The reduction in leukocyte count caused by imatinib primarily reflects suppression of the CML clone. When there is significant (grade 3-4) neutropenia, imatinib should be discontinued until there is neutrophil count recovery. Imatinib should never be reduced, as this increases the risk of selecting a resistant clone. With severe neutropenia, growth factor support can be employed to accelerate recovery. Imatinib can cause liver function abnormalities but it is not recommended that the drug be discontinued unless the increase in liver function tests is greater than 2.5-5 times the baseline normal value.

Differential Diagnosis

Myelofibrosis

Myelofibrosis is a reactive, reversible process that is associated with a wide variety of benign and malignant disorders but whose presence makes it very difficult to define the underlying process causing it. Additionally, myelofibrosis is part of the terminal transformation process of many hematologic malignancies. Thus, the clinical picture described above is compatible with any of the listed diagnostic possibilities. However, the normal platelet count, the basophilia and the leukoerythroblastic reaction presence of a myeloproliferative process such as CML, which can present in blast crisis.

CML should always be a diagnostic consideration in patients such as this one because imatinib is an effective adjunctive therapy in combination with conventional chemotherapy when CML presents in this fashion, in contrast to the lack of success of conventional chemotherapy for the other illnesses listed above.

***

Typically, in CML, the peripheral blood contains the full spectrum of differentiating neutrophils from myeloblasts, promyelocytes, myelocytes, metamyelocytes and bands to mature neutrophils, with a greater proportion of myelocytes than metamyelocytes. An increase solely of neutrophils and band forms is more typical of the rare disorder, CNL, and an increase of monocytes of 1,000/μL or greater is usually considered a hallmark of CMMoL. IMF, of course, can present with a neutrophilic leukocytosis, anemia and splenomegaly and all of these diseases are most common in older men.

The balanced translocation between the long arms of chromosomes 9 and 22, which is both necessary and sufficient for the CML phenotype, is variable with respect to the location of the breakpoint in the bcr gene on chromosome 22. In most CML patients, the position of the breakpoint is such that the BCR-ABL fusion protein has a molecular mass of 210 kDa (p210). In some patients, however, the breakpoint gives rise to BCR-ABL fusion proteins with molecular masses of 230 kDa (p230) or 190 kDa.

These less common fusion proteins are associated with features that mimic CNL (p230) or CMMoL (p190). The patient described above fits the p185 phenotype. While rare, it is important to consider CML in the differential diagnosis of CNL, CMMol and IMF because of the availability of targeted therapy in the form of imatinib and other newer bcr-abl inhibitors such as dasatinib.

***

*** A 56-year-old man with chronic phase CML complains of the sudden onset of shortness of breath, pleuritic chest pain and a low grade fever. The patient had been intolerant of imatinib as the result of intractable diarrhea and was started on interferon alpha. However, because of a leukocyte count of 85,000/μL and night sweats, he was also started on hydroxyurea and allopurinol. Three days after starting the hydroxyurea and interferon, he presents with complaints of the sudden onset of left upper quadrant pain, pleuritic chest pain, dyspnea and fever. The physical examination reveals a dyspneic, diaphoretic man with a temperature of 100.4°F, respirations of 20/minute, a blood pressure of 140/90 and a pulse rate of 120 beats per minute. There is tenderness over the left trapezius muscle, and respiratory splinting with dullness and diminished breath sounds over the left lower lobe. There was a sinus tachycardia but no murmurs or gallops were heard. The spleen was easily felt at 10 cm below the left costal margin with marked tenderness laterally. A rub was heard over the 11th rib laterally. The liver was not enlarged and bowel sounds were present. The extremities showed no edema or cords. The hemoglobin is 12 g %, the leukocyte count 65,000/μL and the platelet count 465,000/μL. A urinalysis is normal. A chest x-ray reveals elevation of the left diaphragm and a small left pleural effusion. Abdominal x-rays reveal no free air. An ECG is normal and the arterial oxygen tension is 95 mm Hg.

Pulmonary embolism with infarction is always a diagnostic consideration with this type of clinical presentation but usually pulmonary infarction occurs in the setting of cardiac failure, which is not the situation here. This is a classical presentation for splenic infarction, which occurs when the spleen outgrows its blood supply. In this instance, the patient’s disease had not yet been brought under control with hydroxyurea and interferon. The possibility of pneumonia must always be considered with this clinical presentation but the absence of a pulmonary infiltrate makes this diagnosis unlikely. Gastric perforation should be included in the differential diagnosis, particularly with the signs of diaphragmatic irritation but the absence of free air on x-ray and the presence of bowel sounds make the diagnosis unlikely. A uric acid stone could present acutely with abdominal pain but the presence of pulmonary symptoms and signs, a normal urinalysis and the administration of allopurinol make this diagnosis unlikely.

This patient has Splenic infarction.

Risk Factors

Only ionizing radiation is a risk factor for the development of CML.

***

  • Drug-induced toxic epidermal necrolysis (TEN) or the Stevens-Johnson syndrome, which is a less severe form of TEN, are immunologically-mediated drug reactions and not dose-related.They thus require immediate and permanent withdrawal of the offending drug and institution of steroid therapy as well as intensive management of the skin desquamation.

***

  • Low dose interferon alpha therapy (3 MIU three times a week) is equivalent to and better tolerated than 5 MIU given daily. Unlike imatinib, the effects of interferon on the bone marrow persist after it is discontinued and it can be given safely during pregnancy. When discontinued for more than 90 days, interferon therapy does not interfere with bone marrow transplantation.
  • No organ system is spared interferon toxicity but many of its side effects develop insidiously and are easy to overlook initially. This is particularly true for hypothyroidism and renal failure. Other side effects such as atrial fibrillation can occur suddenly.

***

***A 19-year-old man complains of a persistent, painful penile erection for over 19 hours. The patient has been in otherwise good health and denies the use of any performance-enhancing drugs. A complete blood count reveals an hematocrit of 39%, a leukocyte count of 380,000/μL with a differential count of 47% neutrophils, 11% bands, 5% metamyelocytes, 19% myelocytes, 5% promyelocytes, 2% blast cells, 5% monocytes and 6% lymphocytes and a platelet count of 147,000/μL.

Priapism is a rare complication of leukostasis in CML, which, if not reversed promptly, can result in erectile dysfunction. The most successful therapeutic approach to the resolution of priapism involves both systemic and local therapy. Thus, in the clinical situation described above, local aspiration and irrigation, followed by phenylephrine injection, should be initiated immediately while leukapheresis is being arranged. Hydroxyurea should be administered concurrently to insure that there is no rebound leukocytosis.

Thanks for reading,

Best regards

Michael

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