MMSE OSCE cases. Anemias

Mini-Mental Status Examination

20XX

OSCE

START

Good Candidates for MMSE assessment

CASE A: Kelly Mitchell 68yo

Chief Complaint: Started gradually with reduced processing speed, difficulty with spatial perception, impaired language comprehension, anomia, and grammatical errors for the past 2 years. Medical background: Hyperlipidemia (under stabilization, and currently well controlled through dietary adjustment).

CASE B: Danielle Mitchell 70yo

Chief Complaint: The patient has experienced a gradual onset of impaired language comprehension, anomia, and grammatical errors for the past 2 years. Medical Background: family history of dementia (mother) and hyperlipidemia, which is currently under stabilization and well-controlled through dietary adjustments.

CASE C: Quinn Chang 69yo

Chief Complaint: The patient has gradually developed impaired episodic memory, topographical disorientation (spatial disorientation), and executive dysfunction for the past 3 years. Medical Background: The patient carries the APOE ε4 allele and experienced a head contusion 20 years ago (it occurred during a motor vehicle accident).

CASE D: Avery Rodriguez 74yo

Chief Complaint: The patient began gradually 7 years ago, marked by impaired multitasking, difficulty with daily planning and memory issues. Medical Background: Family history of frontotemporal dementia (father), history of smoking (persisted for 20 years but was discontinued a decade ago).

CASE E: Peyton O´Connor 69yo

Chief Complaint: Chronic and progressive episodic memory impairment and frequent episodes of disorientation over the past 2 years. Medical background: History of stroke (ischemic stroke that occurred 8 years ago).

CASE F: Taylor Johnson 71yo

Chief Complaint: started gradually losing their train of thought, difficulty multitasking, episodic memory issues for over the past 6 years. Medical background: Family history of frontotemporal dementia (father)

CASE G: Alex Taylor 75yo

Chief Complaint: Started gradually with struggling to find the right words when talking, difficulty multitasking, memory issues, taking longer to think. Medical background: Lead exposure 30 years ago, prior head injury 30 years ago (falling off a bicycle and hitting the head on the pavement).

CASE H: Hayden Thompson 72yo

Chief Complaint: Progressive decline in short term memory leaving constantly the doors unlocked, forgetting to take their medications, in mathematical abilities and difficulty with basic calculations for the past 5 years. Medical background: Family history of Alzheimer's disease (uncle), and hypercholesterolemia (under stabilization, and currently well controlled through dietary adjustment).

CASE I: Skyler Martinez 78yo

Chief Complaint: Difficulty with complex problem-solving over the last 4 years. The patient noted progressive impaired executive functions, reduced cognitive flexibility, poor working memory, and attention deficits. Medical background: History of lacunar stroke (occurred 8 years ago).

CASE J: Morgan Anderson 67 yo

Chief Complaint: Increasing difficulty recognizing familiar faces, visual agnosia, and difficulty with facial recognition. Medical background: History of head contusion 5 years ago (slipped and fell on a wet surface in the restroom), overweight.

Question 10: Write a sentence (samples)

Item 10: Sentence Writing

Item 10: Sentence Writing

Item 10: Sentence Writing

Item 10: Sentence Writing

Item 10: Sentence Writing

Item 10: Sentence Writing

Question 11: Pentagons

Not good Candidates for MMSE assessment

CASE: Mitch Joseph 25 yo

No cognitive complaints or concerns.

CASE: Lee Roberts 70yo

Chief Complaint: Aute innatention, sudden aggressiveness, sudden disorientation, and disorganized thinking Medical Background: COPD and ongoing neumonia

CASE: Cameron Renaud 69yo

Chief Complaint: Memory loss, French-speaking patient

CASE: Jean Rodriguez 74yo

Chief Complaint: Ongoing septic shock. impaired multitasking and memory issues.

Case #6

Patient Name: Mr. Henry Reynolds Age: 64 Presenting Complaint: Constant forgetfulness, slower thinking, delayed recall, apathy Chief Concern: Mr. Henry Reynolds, a 64-year-old male with a five-year history of diabetes mellitus managed with frequent insulin injections (2 times a day), has been brought to your office by his concerned spouse. She reports that her father has been experiencing persistent forgetfulness, noticeably slower thinking, difficulty recalling information, forgetting to eat, and having apathetic behavior. His daughter has observed a decline in his cognitive function over the past 5 years, leading to concerns about his memory and overall cognitive health. These changes have also been accompanied by behavioral alterations.

To address the chief complaint, the patient has been brought to your office by his spouse.

Case #6: Debriefing

Clinical Assessment:

1. As the attending physician, your initial focus is to determine Mr. Reynolds' underlying causes of his cognitive and behavioral changes.
2. It is crucial to thoroughly review Mr. Reynolds' medical history, specifically focusing on medications that may impair his cognitive function such as his diabetes management, and insulin therapy.
3. If hypoglycemia is detected, that is a medical emergency and should be resolved immediately, after this medical condition is treated and reverted, and once the patient is free from any other drugs side effects, conduct a comprehensive cognitive function test, memory, thinking speed, and behavior.
4. Evaluate his insulin regimen, dosages, and potential side effects the medications, which might contribute to cognitive changes.
5. Evaluate and potentially adjust Mr. Reynolds' diabetes management to optimize glycemic control and minimize cognitive complications.

6. Addressing Mr. Reynolds' tendency to forget to eat, is crucial for his overall well-being and may require to prioritize his medication review and optimizing his diabetes management to prevent cognitive impairment due to low blood sugar.7. Additionally, educate the patient on insuling injection technique, also support for Mr. Reynolds and his spouse are essential components of his care plan.

Case # 7 Any volunteers?

Case #7

Patient Name: Mr. Terry Anderson Age: 74 Presenting Complaint: Memory issues, forgetfulness, difficulty paying bills and taking medications, denial of symptoms Chief Concern: Mr. Anderson Terry, a 74-year-old male, has a history of chronic high blood pressure for the past 10 years, managed with metoprolol (25 milligrams daily), and high cholesterol levels for the past five years, treated with diet modifications. He is brought to the office by his daughter, who is concerned about his worsening forgetfulness. Mr. Terry is having trouble remembering family names, paying his bills, and taking his medications. These memory issues have been progressing, and last week, he was found lost in a shopping mall by a neighbor, although he denies the incident. Physical examination: RR: 19, O2 Sat: 94%, HR: 58, the patient exhibits marked bradylalia and bradipsiquia

To address the chief complaint, the patient has been brought to your office by his spouse.

Case #7

Regarding the next steps, if the patient displays any neurological deficits during the consultation, it is imperative to confirm the underlying cause, consider a diagnosis, and promptly initiate appropriate treatment. This is particularly important if the onset of these deficits is sudden. In Mr. Anderson's case, he exhibited an evident monoparesis of the right upper limb during the interview. Given this observation and considering his vascular risk factors, it's crucial to rule out the possibility of a stroke. If a stroke is suspected and ongoing, the cognitive assessment should be temporarily suspended until the primary neurological condition is stabilized."

As the attending physician, paying attention to the patient´s chronic high blood pressure and cholesterol history, it is vital Hold on Cognitive Assessment: If an acute neurological condition, such as a stroke, is suspected, hold the cognitive assessment until the primary neurological condition is stabilized.

Examine the potential impact of metoprolol (bradycardia) on cognitive function and explore if there are side effects contributing to memory issues.

Case # 8 Any volunteers (bilingual english-spanish doctor)?

Case #8

Patient name: Soraia Pereira Age: 73 Presenting complaint: memory issues

The patient is brought to your office by her son due to her profound memory issues that have been ongoing for the past decade. These memory deficits have been progressive and disabling. It all began with her inability to recall events that had transpired mere minutes earlier. Over time, she started to forget essential dates and crucial details. Presently, she is grappling with the distressing challenge of recognizing the faces of her family members. Additionally, it's important to note that this patient has a history of chronic arthritis. As needed, she takes Tylenol, troughly once a month, to alleviate her symptoms.

*** Note #1: the patient resides in Brazil and exclusively speaks Portuguese, her son is proficient in both Portuguese and has some knowledge of English and Spanish

*** Note #2: Please also be aware that the nurse on duty can provide you with the Mini-Mental State Examination (MMSE) in either Portuguese, Spanish, or English versions, depending on your language preferences and needs

MMSE portuguese version

MMSE spanish version

Case #8

As a physician, it's essential to recognize that when encountering a patient who speaks a different language, it is not permissible to perform the Mini-Mental State Examination (MMSE) unless you are proficient in both the patient's language and culture. In cases where proficiency is lacking, it is crucial to refer the patient to a physician who is proficient in the patient's language and culture. Attempting to translate the MMSE with a translator (e.g., google translator) can introduce bias, as it may not fully consider the patient's cultural and contextual nuances.

Last question: Among the presented scenarios, which one is the most indicative of a potential dementia case, and what type of dementia is likely to be involved?

Optional activity: Among the presented scenarios, which one is the most indicative of a potential dementia case, and what type of dementia is likely to be involved?

When to apply the MMSE

YES

NO !!!!!

A 62 yo patient with reported memomry issues due to medications side effects

A 53-year-old patient with reported memory lapses due to sleep apnea and poor sleep quality.

A 68-year-old patient with post-traumatic stress disorder experiencing constant memory problems.

A 55-year-old patient with attention deficit hyperactivity disorder (ADHD) experiencing short-term memory lapses

A 67-year-old patient with acute impaired attention and focus issues

A 61-year-old patient with a history of substance abuse showing transient memory problems

An 80-year-old patient with severe aphasia and memory loss.

A 60-year-old patient with Down syndrome showing a decline in cognitive function

In the decline of a failing brain, we witness the gradual fading of one's essence. Let our response be one of kind humanity, as we dedicate ourselves to assisting those affected and shielding others from its grasp. Thank you !!!! Gonzalez MD

Morphological Abnormalities of Red Blood Cells

Size : approx. same as nucleus of mature small lymphocyte.

ERSpublications A review of ventilation–perfusion relationships and gas exchange, basic concepts and their relation to clinical cases http://ow.ly/wMUwq

Morphological Abnormalities of Red Blood Cells

ERSpublications A review of ventilation–perfusion relationships and gas exchange, basic concepts and their relation to clinical cases http://ow.ly/wMUwq

Variations in Size

ERSpublications A review of ventilation–perfusion relationships and gas exchange, basic concepts and their relation to clinical cases http://ow.ly/wMUwq

Variations in Size

ERSpublications A review of ventilation–perfusion relationships and gas exchange, basic concepts and their relation to clinical cases http://ow.ly/wMUwq

Variations in Size

The most important red cell index for discussing the variations in size of blood cells is the Mean Corpuscular Volume. Just to refresh, the MCV is the average volume of a red blood cell. It is reflective of the size of a cell, and thus, a large MCV indicates a large red blood cell, and a small MCV indicates a small red blood cell. Its typical reference value is 80fL – 95fL, though some sources use 100fL as the upper limit. Any variation in size of the RBCs is known as anisocytosis, and the degree of anisocytosis in a sample of blood is known as the red cell distribution width (RDW).

Furthermore, it is useful for calculating the red blood cell distribution width (RDW).

normal MCV is between 80 to 100 fL

MCV can determine the classification of anemia as either microcytic anemia with MCV below the normal range, normocytic anemia with MCV within the normal range, macrocytic anemia with MCV above the normal range

varying MCVs, the causes of microcytic, macrocytic, and normocytic anemias

It has utility in helping determine the etiology of anemia

ERSpublications A review of ventilation–perfusion relationships and gas exchange, basic concepts and their relation to clinical cases http://ow.ly/wMUwq

Variations in Size: MCV

The most important red cell index for discussing the variations in size of blood cells is the Mean Corpuscular Volume. Its reference value: 80fL – 95fL (100fL) Any variation in size of the RBCs is known as anisocytosis, and the degree of anisocytosis in a sample of blood is known as the red cell distribution width.

A varying MCVs: microcytic, macrocytic, and normocytic anemias

Utility in helping determine the etiology of anemia

ERSpublications A review of ventilation–perfusion relationships and gas exchange, basic concepts and their relation to clinical cases http://ow.ly/wMUwq

Variations in Size: Isocytosis

Red blood cells normally are the same size and color and are a lighter color in the center.

Abnormal results mean the size, shape, color, or coating of the red blood cells is not normal. Some abnormalities may be graded on a 4-point scale: 1+ one quarter of cells are affected 2+ one half of cells are affected 3+ three quarters of cells are affected 4+ all of the cells are affected

ERSpublications A review of ventilation–perfusion relationships and gas exchange, basic concepts and their relation to clinical cases http://ow.ly/wMUwq

Variations in Size: Isocytosis vs Anisocytosis

ERSpublications A review of ventilation–perfusion relationships and gas exchange, basic concepts and their relation to clinical cases http://ow.ly/wMUwq

Anisocytosis //// Importance ??????

Anisocytosis leads to reduced oxygen delivery to the peripheral tissues

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RBC calculations & indices

Calculation of the MCV value is by multiplying the percent hematocrit by ten divided by the erythrocyte count.

ERSpublications A review of ventilation–perfusion relationships and gas exchange, basic concepts and their relation to clinical cases http://ow.ly/wMUwq

RBC calculations & indices

1. Hb 2. Hct 3. MCV 4. RDW 5. Retic

1. Anemia Y/N 2. Anemia Y/N 3. Volume 4. Volume 5. BM FUNCTION

ERSpublications A review of ventilation–perfusion relationships and gas exchange, basic concepts and their relation to clinical cases http://ow.ly/wMUwq

Variations in Size/ RDW

It is a measure of red blood cell volume variations (anisocytosis) and is reported as part of a standard complete blood smears The importance of RDW as a predictor of poor clinical outcomes in the settings of various diseases

RDW changes occur: Early in anaemias (Renal, Cardiac, respiratory, hypoxic, malignant) and other diseases and also with age. Inflammation is a factor, the level of C-reactive protein is raised more or less in parallel with the RDW

RDW is elevated in accordance with variation in red cell size; that is, when elevated RDW is reported, marked anisocytosis (increased variation in red cell size) is expected on peripheral blood smear review. The reference range for RDW is as follows: RDW-SD 39-46 fL RDW-CV 11.6-14.6% in adult

ERSpublications A review of ventilation–perfusion relationships and gas exchange, basic concepts and their relation to clinical cases http://ow.ly/wMUwq

Variations in Size/ RDW

ERSpublications A review of ventilation–perfusion relationships and gas exchange, basic concepts and their relation to clinical cases http://ow.ly/wMUwq

Variations in Size/ RDW

That's why indices results are usually combined with other blood measurements. This combination of results can provide a more complete picture of the health of your red blood cells and can help diagnose a variety of conditions

ERSpublications A review of ventilation–perfusion relationships and gas exchange, basic concepts and their relation to clinical cases http://ow.ly/wMUwq

Microcyte (not microcytosis - not microcytic)

A microcyte, is a red blood cell by definition, a small (micro-) mature cell (-cyte). In terms of MCV, a microcyte has an MCV below 80fL. In terms of actual diameter, a microcyte is defined as any RBC with a diameter less than 5.0 microns (average of 7.2 microns). Microcytes indicate some problem with the manufacturing system of red blood cells (deficiency). The diseases include: Iron Deficiency Anemia Sideroblastic Anemia Beta thalassemias Lead Poisoning

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Microcyte (not microcytosis - not microcytic)

Deficiency of iron leads to a scenario where the red blood cell cannot be filled with Hb and thus is an overall smaller cell, since there is less Hb. Sideroblastic Anemia (bone marrow releases immature red blood cells, sideroblasts). These sideroblasts have rings of iron around their nucleus, and thus the iron is used up on the sideroblasts causing often a defiency of iron leading to red blood cells that do mature, becoming microcytes. Beta thalassemias (the beta chain of Hb is usually missing or deformed/blockage to the HBB gene --- leads to decreased Beta-chain synthesis ---- leads to the underproduction of HBA --- Reductions in HBA to fill the red blood cells ------ in turn leads to microcytic anemia). Lead Poisoning: lead interferes with the activity of delta-aminolevulinic acid dehydratase (ALAD) and ferrochelatase, both involved in the formation of heme. Microcytosis occurs due to lack of heme, which leads to a lack of Hb and thus a deficiency, causing smaller RBCs.

ERSpublications A review of ventilation–perfusion relationships and gas exchange, basic concepts and their relation to clinical cases http://ow.ly/wMUwq

B thalassemia

Beta thalassemias (the beta chain of Hb is usually missing or deformed/blockage to the HBB gene --- leads to decreased Beta-chain synthesis ---- leads to the underproduction of HBA --- Reductions in HBA to fill the red blood cells ------ in turn leads to microcytic anemia).

ERSpublications A review of ventilation–perfusion relationships and gas exchange, basic concepts and their relation to clinical cases http://ow.ly/wMUwq

Lead poisoning

Lead Poisoning: lead interferes with the activity of delta-aminolevulinic acid dehydratase (ALAD) and ferrochelatase, both involved in the formation of heme. Microcytosis occurs due to lack of heme, which leads to a lack of Hb and thus a deficiency, causing smaller RBCs.

ERSpublications A review of ventilation–perfusion relationships and gas exchange, basic concepts and their relation to clinical cases http://ow.ly/wMUwq

B thalassemia

ERSpublications A review of ventilation–perfusion relationships and gas exchange, basic concepts and their relation to clinical cases http://ow.ly/wMUwq

Lead poisoning

ERSpublications A review of ventilation–perfusion relationships and gas exchange, basic concepts and their relation to clinical cases http://ow.ly/wMUwq

??????? low MCV, High RDW = ???

ERSpublications A review of ventilation–perfusion relationships and gas exchange, basic concepts and their relation to clinical cases http://ow.ly/wMUwq

Iron deficiency anemia

ERSpublications A review of ventilation–perfusion relationships and gas exchange, basic concepts and their relation to clinical cases http://ow.ly/wMUwq

RBC calculations & indices

ERSpublications A review of ventilation–perfusion relationships and gas exchange, basic concepts and their relation to clinical cases http://ow.ly/wMUwq

RBC calculations & indices: Iron - Hb defects (filling defects: MCV + RDW

ERSpublications A review of ventilation–perfusion relationships and gas exchange, basic concepts and their relation to clinical cases http://ow.ly/wMUwq

Macrocyte: Immature cells --- DNA synthesis impairment

A large (macro-) mature cell (-cyte).In terms of MCV, a macrocyte has an MCV above 95 (or above the reference range). It is thus an enlargement of red blood cells with a near constant concentration of hemoglobin. Megaloblastic Anemia/////The most common cause of macrocytic anemia, which is the result of impaired DNA synthesis. Although DNA synthesis is impaired, RNA synthesis is not, and RNA continues to be produced, increasing the nuclear matter within RBCs that is not being converted to DNA. Thus, the cell gradually enlarges due to increased nuclear matter, causing macrocytosis. Vitamin B12 deficiency and Folate deficiency (synthesis of Thymidine and Purines), and thus DNA synthesis is impaired in these deficiencies Aplastic Anemia Mild macrocytosis is seen in recovery from aplastic anemia, which occurs when there is a bone marrow pathology and a deficiency of all 3 types of blood cells (WBC, RBC, platelets) occurs. Neonates Observe macrocytes below:

What is a megaloblast???????

Daily folate requirement:100µg Daily B-12 requirement:1µg

ERSpublications A review of ventilation–perfusion relationships and gas exchange, basic concepts and their relation to clinical cases http://ow.ly/wMUwq

Dumping syndrome ?????

ERSpublications A review of ventilation–perfusion relationships and gas exchange, basic concepts and their relation to clinical cases http://ow.ly/wMUwq

RBC calculations & indices

ERSpublications A review of ventilation–perfusion relationships and gas exchange, basic concepts and their relation to clinical cases http://ow.ly/wMUwq

Reticulocyte COUNT and index

The number of reticulocytes is an accurate reflection of the amount of RBC produced in bone marrow and entering the peripheral blood. It is therefore an index of effective erythropoiesis. Normal fraction is low (0.5% to 2.5% in adults and 2% to 6% in infants) because there is a homeostasis between destruction of aged abnormal RBC and a low level of marrow activity required to maintain normal hemoglobin levels

If the patient has moderate or severe anemia, the bone marrow will release reticulocytes prematurely into the blood “shift reticulocytes”, and they will circulate in the peripheral blood for longer than normallyreleased reticulocytes. In such case a corrected count expressed as reticulocyte index or reticulocyte proliferation index to avoid spurious results.

RBC calculations & indices

ERSpublications A review of ventilation–perfusion relationships and gas exchange, basic concepts and their relation to clinical cases http://ow.ly/wMUwq

Reticulocyte COUNT and index. Interpretation

Interpretation: RI <2% with anemia indicates decreased production of reticulocytes (i.e. inadequate response to correct the anemia) and therefore RBCs. RI >3% with anemia indicates loss of RBCs (from causes such as hemolysis, bleeding etc.) with an increased compensatory production of reticulocytes to replace the lost RBC

Reticulocyte percentage vs absolute COUNT

The reticulocyte count is used to estimate the degree of effective erythropoiesis, which can be reported as absolute reticulocyte count or as a reticulocyte percentage. if anemia is present, the reticulocyte percentage is spuriously high and may not reflect true bone marrow responses to anemia; therefore, the value has to be adjusted to a corrected reticulocyte percentage based on the patient’s hematocrit (automated hematology analyzer), Another factor that can result in spuriously elevated reticulocyte percentage and absolute reticulocyte count is the time reticulocytes spend in the blood circulation prior to maturation. In general, reticulocytes mature within one day of being released from bone marrow; however, in the setting of stress erythropoiesis, as in a high erythropoietin level, reticulocytes are prematurely released from bone marrow to the blood circulation, increasing the number of days that reticulocytes stay in the blood circulation (maturation time of reticulocytes in days) and resulting in a spuriously high reticulocyte count. The reticulocyte index, is a calculation that helps to alleviate the effect of the premature release of reticulocytes by taking into account maturation time of reticulocytes (ie, correction factor), in addition to correcting for the degree of anemia. The absolute reticulocyte count and corrected reticulocyte percentage, as a marker of RBC production, provide an initial evaluation as to whether anemia is due to loss of RBCs or inadequate production. Increased reticulocyte count reflects ongoing or recent RBC production activity, which may result from the following: Post bleeding (trauma, gastrointestinal bleeding, menorrhagia) Post hemolysis (hemolytic anemia, hemolytic disease of the newborn) Response to therapy (iron supplementation, vitamin B-12 or folic acid supplementation, erythropoietin supplementation, bone marrow recovery following chemotherapy or bone marrow transplantation) A decreased reticulocyte count reflects decreased RBC production: Vitamin B-12, folic acid, and iron deficiency (megaloblastic anemia, pernicious anemia, iron deficiency anemia) Decreased erythropoietin level (chronic renal failure) Aplastic anemia or bone marrow failure syndromes Post radiation therapy Bone marrow replacement by benign (metabolic storage diseases, infection, sarcoidosis) or malignant processes (leukemias, involvement by lymphomas or metastatic tumors)

Reticulocyte COUNT and index

Reticulocyte index (also known as the reticulocyte production index) The reticulocyte index is another parameter that provides an assessment for adequate bone marrow response to anemia. An increased RPI (RPI >3) can be seen in the following scenarios: Hemolytic anemias Recent hemorrhage Marrow response to therapy A decreased RPI (RPI < 2) can be seen in the following: Hypoproliferative disorder (ie, aplastic anemia) Ineffective erythropoiesis, as seen in megaloblastic anemia Immature reticulocyte fraction Immature reticulocyte fraction is a quantitative measurement of the RNA content of the reticulocytes: to differentiate megaloblastic anemia or myelodysplasia

Reticulocyte COUNT and index

A sample haemogram report of an adult male from an automated hematology analyser The uncorrected reticulocyte count was 3.59%, which is higher than the normal range for adults; this may give a false interpretation of an adequate reticulocyte response from the bone marrow; however, after correction for hematocrit the reticulocyte index was 2%

Part II: Poikilocytosis

Myelodysplastic Syndrome

Myelodysplastic Syndrome

Heterogeneous group of clonal hematopoietic disorders commonly found in the aging population. All are characterized by one or more peripheral blood cytopenias. Bone marrow is usually hypercellular Bone marrow cells display aberrant morphology and maturation (dysmyelopoiesis), resulting in ineffective blood cell production. MDS affects hematopoiesis at the stem cell level, as indicated by cytogenetic abnormalities, molecular mutations, and morphologic and physiologic abnormalities in maturation and differentiation of one or more of the hematopoietic cell lines.

Myelodysplastic Syndrome

MDS may involve one, two, or all three myeloid hematopoiesis cell lineages—erythrocytic, granulocytic, megakaryocytic—depending on the subtype and stage of the disease. The heterogeneity of MDS reflects the fact that its course involves a series of cytogenetic events that can result in the transformation of MDS into acute myeloid leukemia. Thus, although MDS is clonal, it is considered a premalignant condition. Patients with MDS may present with clinical manifestations of anemia, thrombocytopenia, and/or neutropenia The workup in patients with possible MDS includes a complete blood count with differential, peripheral blood smear, and bone marrow studies. Supportive therapy, including transfusions, and may include bone marrow stimulation and cytotoxic chemotherapy or hypomethylating agents. Bone marrow transplantation has a limited role

Practice Essentials Chronic myelogenous leukemia (CML), also known as chronic myeloid leukemia, is a myeloproliferative disorder characterized by increased proliferation of the granulocytic cell line without the loss of their capacity to differentiate. Consequently, the peripheral blood cell profile shows an increased number of granulocytes and their immature precursors, including occasional blast cells. CML accounts for 20% of all leukemias affecting adults. See the image below.

Chronic myelogenous leukemia. Blood film at 1000X magnification demonstrates the whole granulocytic lineage, including an eosinophil and a basophil. Courtesy of U. Woermann, MD, Division of Instructional Media, Institute for Medical Education, University of Bern, Switzerland. View Media Gallery See Chronic Leukemias: 4 Cancers to Differentiate, a Critical Images slideshow, to help detect chronic leukemias and determine the specific type present. Signs and symptoms The clinical manifestations of CML are insidious, changing somewhat as the disease progresses through its 3 phases (chronic, accelerated, and blast). Patients in the chronic phase may be asymptomatic or may display any of the following signs and symptoms: Fatigue, weight loss, loss of energy, decreased exercise tolerance Low-grade fever and excessive sweating from hypermetabolism Elevated white blood cell (WBC) count or splenomegaly on routine assessment Early satiety and decreased food intake from encroachment on stomach by enlarged spleen Left upper quadrant abdominal pain from spleen infarction Hepatomegaly

Background CML is one of the few cancers known to be caused by a single, specific genetic mutation. More than 90% of cases result from a cytogenetic aberration known as the Philadelphia chromosome (see Pathophysiology). CML progresses through three phases: chronic, accelerated, and blast. In the chronic phase of disease, mature cells proliferate; in the accelerated phase, additional cytogenetic abnormalities occur; in the blast phase, immature cells rapidly proliferate. [1, 2] Approximately 85% of patients are diagnosed in the chronic phase and then progress to the accelerated and blast phases after 3-5 years. The diagnosis of CML is based on the histopathologic findings in the peripheral blood and the Philadelphia chromosome in bone marrow cells (see Workup). CML accounts for 20% of all leukemias affecting adults. It typically affects middle-aged individuals. Uncommonly, the disease occurs in younger individuals. Younger patients may present with a more aggressive form of CML, such as in accelerated phase or blast crisis. Uncommonly, CML may appear as a disease of new onset in elderly individuals. The goals of treatment are to achieve hematologic, cytogenetic, and molecular remission. Although a variety of medications have been used in CML, including myelosuppressive agents and interferon alfa, tyrosine kinase inhibitors (TKIs), starting with the first-generation TKI imatinib, have become the agents of choice in CML. They are playing increasingly important roles in inducing complete remission, which can allow cessation of therapy and excellent response if disease returns. TKIs are slowly replacing allogeneic hematopoietic stem cell transplantation as a proven cure for CML. (See Treatment.)

Pathophysiology CML is an acquired abnormality that involves the hematopoietic stem cell. It is characterized by a cytogenetic aberration consisting of a reciprocal translocation between the long arms of chromosomes 22 and 9 [t(9;22)]. The translocation results in a shortened chromosome 22, an observation first described by Nowell and Hungerford and subsequently termed the Philadelphia (Ph1) chromosome after the city of discovery. (See the image below.) The Philadelphia chromosome, which is a diagnostic The Philadelphia chromosome, which is a diagnostic karyotypic abnormality for chronic myelogenous leukemia, is shown in this picture of the banded chromosomes 9 and 22. Shown is the result of the reciprocal translocation of 22q to the lower arm of 9 and 9q (c-abl to a specific breakpoint cluster region [bcr] of chromosome 22 indicated by the arrows). Courtesy of Peter C. Nowell, MD, Department of Pathology and Clinical Laboratory of the University of Pennsylvania School of Medicine. View Media Gallery This translocation relocates an oncogene called ABL from the long arm of chromosome 9 to a specific breakpoint cluster region (BCR) in the long arm of chromosome 22. The ABL oncogene encodes a tyrosine protein kinase. The resulting BCR-ABL fusion gene encodes a chimeric protein with strong tyrosine kinase activity. The expression of this protein leads to the development of the CML phenotype, through processes that are not yet fully understood. [3, 4, 5, 6, 7, 8, 9, 10, 2] The presence of BCR-ABL rearrangement is the hallmark of CML, although this rearrangement has also been described in other diseases. It is considered diagnostic when present in a patient with clinical manifestations of CML. The initiating factor of CML is still unknown, but exposure to ionizing radiation has been implicated, as observed in the increased prevalence among survivors of the atomic bombing of Hiroshima and Nagasaki. Other agents, such as benzene, are possible causes.

Epidemiology The American Cancer Society (ACS) estimates that 8930 new cases of CML will be diagnosed in 2023, 5190 in males and 3740 in females. The ACS estimates that 1220 deaths from CML will occur in 2022, 670 in males and 550 in females. [11] Incidence and mortality rates for CML did not change significantly over 2009–2019; based on 2016–2020 data, the age-adjusted rate of new cases was 1.9 per 100,000 population per year, and the death rate was 0.3 per 100,000 population per year. [12]

History The clinical manifestations of chronic myelogenous leukemia (CML) are insidious. The disease is often discovered incidentally in the chronic phase, when an elevated white blood cell (WBC) count is revealed by a routine blood count or when an enlarged spleen is found on a general physical examination. Nonspecific symptoms of fatigue and weight loss may occur long after the onset of the disease. Loss of energy and decreased exercise tolerance may occur during the chronic phase after several months. Patients often have symptoms related to enlargement of the spleen, liver, or both. The large spleen may encroach on the stomach and cause early satiety and decreased food intake. Left upper quadrant abdominal pain described as "gripping" may occur from spleen infarction. The enlarged spleen may also be associated with a hypermetabolic state, fever, weight loss, and chronic fatigue. The enlarged liver may contribute to the patient's weight loss. Some patients with CML have low-grade fever and excessive sweating related to hypermetabolism. In some patients who present in the accelerated, or acute, leukemia phase of the disease (skipping the chronic phase), bleeding, petechiae, and ecchymoses may be the prominent symptoms. In these situations, fever is usually associated with infections. Bone pain and fever, as well as an increase in bone marrow fibrosis, are harbingers of the blast phase. Physical Examination Splenomegaly is the most common physical finding in patients with CML. In more than 50% of the patients with CML, the spleen extends more than 5 cm below the left costal margin at time of discovery. The size of the spleen correlates with the peripheral blood granulocyte counts, with the largest spleens being observed in patients with high WBC counts. A very large spleen is usually a harbinger of the transformation into an acute blast crisis form of the disease. Hepatomegaly also occurs, although less commonly than splenomegaly. Hepatomegaly is usually part of the extramedullary hematopoiesis occurring in the spleen. Physical findings of leukostasis and hyperviscosity can occur in some patients, with extraordinary elevation of their WBC counts, exceeding 300,000-600,000 cells/μL. Upon funduscopy, the retina may show papilledema, venous obstruction, and hemorrhages. The blast crisis is marked by an increase in the bone marrow or peripheral blood blast count or by the development of soft-tissue or skin leukemic infiltrates. Typical symptoms are due to increasing anemia, thrombocytopenia, basophilia, a rapidly enlarging spleen, and failure of the usual medications to control leukocytosis and splenomegaly.

Diagnostic Considerations Problems to be considered include the following: Acute myeloid leukemia Chronic myelomonocytic leukemia Chronic neutrophilic leukemia Thrombocythemia Leukemoid reactions from infections (chronic granulomatous [eg, tuberculosis]) Tumor necrosis

Approach Considerations The workup for chronic myelogenous leukemia (CML) consists of a complete blood count with differential, peripheral blood smear, and bone marrow analysis. Although typical hepatomegaly and splenomegaly may be imaged by using a liver/spleen scan, these abnormalities are often so obvious clinically that radiologic imaging is not necessary. The diagnosis of CML is based on the histopathologic findings in the peripheral blood and the Philadelphia (Ph1) chromosome in bone marrow cells. Findings from the workup—in particular, the percentage of blasts in peripheral blood or bone marrow—are used to determine the phase of CML: chronic, accelerated, or blast. For more information, see Chronic Myelogenous Leukemia Staging. Other laboratory abnormalities include hyperuricemia, which is a reflection of high bone marrow cellular turnover, and markedly elevated serum vitamin B12–binding protein (TC-I). The latter is synthesized by the granulocytes and reflects the degree of leukocytosis. Blood Count and Peripheral Smear In CML, the increase in mature granulocytes and normal lymphocyte counts (low percentage due to dilution in the differential count) typically results in a total WBC count of 20,000-60,000 cells/μL. A mild increase in basophils and eosinophils is present and becomes more prominent during the transition to acute leukemia. These mature neutrophils, or granulocytes, have decreased apoptosis (programmed cell death), resulting in accumulation of long-lived cells with low or absent enzymes, such as alkaline phosphatase (ALP). Consequently, the leukocyte alkaline phosphatase stains very low to absent in most cells, resulting in a low score. The peripheral blood smear in patients with CML shows a typical leukoerythroblastic blood picture, with circulating immature cells from the bone marrow (see the image below). Chronic myelogenous leukemia. Blood film at 400X m Chronic myelogenous leukemia. Blood film at 400X magnification demonstrates leukocytosis with the presence of precursor cells of the myeloid lineage. In addition, basophilia, eosinophilia, and thrombocytosis can be seen. Courtesy of U. Woermann, MD, Division of Instructional Media, Institute for Medical Education, University of Bern, Switzerland. View Media Gallery The transitional or accelerated phase of CML is characterized by poor control of blood counts with myelosuppressive medication, the appearance of peripheral blast cells (≥15%), promyelocytes (≥30%), basophils (≥20%), and reduction in platelet counts to less than 100,000 cells/μL unrelated to therapy. Promyelocytes and basophils are shown in the images below. Chronic myelogenous leukemia. Blood film at 1000X Chronic myelogenous leukemia. Blood film at 1000X magnification shows a promyelocyte, an eosinophil, and 3 basophils. Courtesy of U. Woermann, MD, Division of Instructional Media, Institute for Medical Education, University of Bern, Switzerland. View Media Gallery Chronic myelogenous leukemia. Blood film at 1000X Chronic myelogenous leukemia. Blood film at 1000X magnification demonstrates the whole granulocytic lineage, including an eosinophil and a basophil. Courtesy of U. Woermann, MD, Division of Instructional Media, Institute for Medical Education, University of Bern, Switzerland. View Media Gallery Signs of transformation or accelerated phase in patients with CML are poor control of blood counts with therapy, increasing blast cells in peripheral blood with basophilia and thrombocytopenia not related to therapy, new cytogenetic abnormalities, and increasing splenomegaly and myelofibrosis. In approximately two thirds of cases, the blasts are myeloid. However, in the remaining one third of patients, the blasts exhibit a lymphoid phenotype, further evidence of the stem cell nature of the original disease. Additional chromosomal abnormalities are usually found at the time of blast crisis, including additional Ph1 chromosomes or other translocations. Early myeloid cells such as myeloblasts, myelocytes, metamyelocytes, and nucleated red blood cells are commonly present in the blood smear, mimicking the findings in the bone marrow. The presence of the different midstage progenitor cells differentiates CML from the acute myelogenous leukemias, in which a leukemic gap (maturation arrest) or hiatus exists that shows absence of these cells. A mild to moderate anemia is very common at diagnosis and is usually normochromic and normocytic. The platelet counts at diagnosis can be low, normal, or even increased in some patients (>1 million in some). Bone Marrow Analysis The bone marrow is characteristically hypercellular, with expansion of the myeloid cell line (eg, neutrophils, eosinophils, basophils) and its progenitor cells. Megakaryocytes (see the image below) are prominent and may be increased. Mild fibrosis is often seen in the reticulin stain. Chronic myelogenous leukemia. Bone marrow film at Chronic myelogenous leukemia. Bone marrow film at 400X magnification demonstrates clear dominance of granulopoiesis. The number of eosinophils and megakaryocytes is increased. Courtesy of U. Woermann, MD, Division of Instructional Media, Institute for Medical Education, University of Bern, Switzerland. View Media Gallery Cytogenetic studies of the bone marrow cells, and even peripheral blood, should reveal the typical Ph1 chromosome, which is a reciprocal translocation of chromosomal material between chromosomes 9 and 22 (see the image below). This is the hallmark of CML, found in almost all patients with the disease and present throughout the entire clinical course of CML. The Philadelphia chromosome, which is a diagnostic The Philadelphia chromosome, which is a diagnostic karyotypic abnormality for chronic myelogenous leukemia, is shown in this picture of the banded chromosomes 9 and 22. Shown is the result of the reciprocal translocation of 22q to the lower arm of 9 and 9q (c-abl to a specific breakpoint cluster region [bcr] of chromosome 22 indicated by the arrows). Courtesy of Peter C. Nowell, MD, Department of Pathology and Clinical Laboratory of the University of Pennsylvania School of Medicine. View Media Gallery In addition, the chimeric BCR-ABL messenger RNA (mRNA) that characterizes CML can be detected by polymerase chain reaction (PCR). This is a sensitive test that requires just a few cells and is useful in monitoring minimal residual disease (MRD) to determine the effectiveness of therapy. BCR-ABL mRNA transcripts can also be measured in peripheral blood Karyotypic analysis of bone marrow cells requires the presence of a dividing cell without loss of viability because the material requires that the cells go into mitosis to obtain individual chromosomes for identification after banding. This is a slow, labor-intensive process. Fluorescence in situ hybridization (FISH) uses labeled probes that are hybridized to either metaphase chromosomes or interphase nuclei, and the hybridized probe is detected with fluorochromes. This technique is a rapid and sensitive means of detecting recurring numerical and structural abnormalities. (See the image below.) European LeukemiaNet guidelines recommend FISH for use in cases that are Ph1 negative. [20] Chronic myelogenous leukemia. Fluorescence in situ Chronic myelogenous leukemia. Fluorescence in situ hybridization using unique-sequence, double-fusion DNA probes for bcr (22q11.2) in red and c-abl (9q34) gene regions in green. The abnormal bcr/abl fusion present in Philadelphia chromosome–positive cells is in yellow (right panel) compared with a control (left panel). Courtesy of Emmanuel C. Besa, MD. View Media Gallery Two forms of the BCR-ABL mutation have been identified. These vary according to the location of their joining regions on bcr 3' domain. Approximately 70% of patients who have the 5' DNA breakpoint have a b2a2 RNA message, and 30% of patients have a 3' DNA breakpoint and a b3a2 RNA message. The latter is associated with a shorter chronic phase, shorter survival, and thrombocytosis. CML should be differentiated from Ph1-negative diseases with negative PCR results for BCR-ABL mRNA. These diseases include other myeloproliferative disorders and chronic myelomonocytic leukemia, which is now classified with the myelodysplastic syndromes. Additional chromosomal abnormalities, such as an additional or double Ph1-positive chromosome or trisomy 8, 9, 19, or 21; isochromosome 17; or deletion of the Y chromosome, have been described as the patient enters a transitional form or accelerated phase of the blast crisis as the Ph chromosome persists. Patients with conditions other than CML, such as newly diagnosed acute lymphocytic leukemia (ALL) or nonlymphocytic leukemia, may also be positive for the Ph1 chromosome. Some authors consider this the blastic phase of CML without a chronic phase. The chromosome is rarely found in patients with other myeloproliferative disorders, such as polycythemia vera or essential thrombocythemia, but these cases are probably misdiagnosed CML. It is rarely observed in myelodysplastic syndrome.

Approach Considerations The goals of treatment of chronic myelogenous leukemia (CML) are threefold and have changed markedly since the advent of tyrosine kinase inhibitor (TKI) therapy. They are as follows: Hematologic remission (normal complete blood cell count [CBC] and physical examination (ie, no organomegaly) Cytogenetic remission (normal chromosome returns with 0% Philadelphia chromosome–positive (Ph+) cells) Molecular remission (negative polymerase chain reaction [PCR] result for the mutational BCR-ABL mRNA), which represents an attempt for cure and prolongation of patient survival Typically, CML has three clinical phases: an initial chronic phase, during which the disease process is easily controlled; then a transitional and unstable course (accelerated phase); and, finally, a more aggressive course (blast crisis), which is usually fatal. In all three phases, supportive therapy to control symptoms and complications resulting from anemia and thrombocytopenia (eg, with transfusions of red blood cells or platelets) may be used to relieve symptoms and improve quality of life. In Western countries, 90% of patients with CML are diagnosed in the chronic phase. These patients’ white blood cell (WBC) count is usually controlled with medication (hematologic remission). For most patients with chronic-phase CML who are treated with TKIs, median survival is expected to approach normal life expectancy. [1, 23] The standard treatment of choice for chronic phase CML is a TKI: either the first-generation TKI imatinib, which is a specific small-molecule inhibitor of BCR-ABL in all phases of CML, or a second-generation TKI—nilotinib (Tasigna), dasatinib (Sprycel), or bosutinib (Bosulif). Although the second-generation TKIs produce a higher rate of deep molecular response and provide better early control of disease than imatinib, the benefits and risks of these newer agents compared with imatinib, as well as their comparative long-term safety profiles, have not been fully established, [24, 25] and the second-generation TKIs have not been tested against each other. [20] Current National Comprehensive Cancer Network guidelines list imatinib as a preferred agent for low-risk CML and recommend second-generation TKIs as preferred agents for intermediate- and high-risk chronic phase CML. [26] In patients with a durable deep molecular response to TKI therapy, treatment discontinuation may be considered (see Long-Term Monitoring, below). However, only about 20% of patients wich chronic-phase CML achieve treatment-free remission; most patients with CML require lifelong TKI therapy. [20] Some patients with CML progress to a transitional or accelerated phase, which may last for several months. The survival of patients diagnosed in this phase is 1-1.5 years. This phase is characterized by poor control of blood counts with therapy and the appearance of peripheral blast cells (≥15%), promyelocytes (≥30%), basophils (≥20%), and platelet counts less than 100,000 cells/μL unrelated to therapy. Many of the treatment decisions in CML, including possible hematopoietic stem cell transplantation [27] and investigative options for younger patients, are extremely complex and in constant flux. Individualized decisions should be made in conjunction with consultation with physicians familiar with the recent literature. New agents that are currently under study may prolong the survival of patients with CML and offer the possibility of eventual cure. Physicians should refer their patients to tertiary care centers for clinical trials involving these therapies. For more information, see Chronic Myelogenous Leukemia Treatment Protocols. Cost concerns TKIs are expensive and require prolonged use, making drug cost an important issue in CML treatment. Many patients with CML require lifelong TKI therapy—and the life expectancy of patients with CML treated with imatinib, for example, now approaches that of the general population. [23, 28]

The interstitium is certainly more than “mere fibers on the alveolar wall”

ERSpublications A review of ventilation–perfusion relationships and gas exchange, basic concepts and their relation to clinical cases http://ow.ly/wMUwq

Any questions??? karla.belen@edu.uag.mx