Differentiating the causes of weight loss, diarrhoea. Another case another disease.

A 23 year old woman presented to the OPD of her hospital with palpitation. Her description was “My heart thuds so fast that I think it is going to burst. It drums in my ear, goes fast and sometimes slower and takes hours to settle to a steady beat after I have rested for hours, had some water and something to eat and sometimes I have to go to a doctor who gives me some tablets and oxygen to inhale in his clinic I get dizzy and breathless. Sometimes I cough a lot and bring up phlegm tinged with blood. My heart always beats faster than when I was well all the time and goes fast and slow.”

When were you well and what symptoms did you have to begin with before the palpitation began?

She had developed diarrhoea six months ago. She passed 3-6 semi-formed stools a day without mucus or blood. She had a good appetite. had no abdominal cramps and has lost 6 kg weight during this time. She has no fever, night sweats, abdominal bloating, heartburn or rectal discomfort on passing stool. She did not pass urine in excess nor feel unduly thirsty. She lived with her husband who was healthy, her mother in law who had been treated for pulmonary tuberculosis a year back and was now in good health and was asymptomatic. Her two year old son and 5 year old daughter had received BCG vaccination as part of their childhood vaccination program and were in apparent good health. Her husband was the breadwinner. He was a carpenter, rented a comfortable house with electricity and running water and the family ate meat, chicken, vegetables, fruit and dal daily and had access to a government hospital in a nearby town.

What do we need to learn more about the diarrhoea? We know the frequency and consistency and that there is no blood or mucus so is unlikely to be from the large gut or an infection. Is the diarrhoea infective, inflammatory in nature or non-inflammatory? Is it secretory or osmotic or malabsorptive in character? There is no fever, night sweats, abdominal pain or colic. She does not complain of proctitis i.e. pain during defecation and does not give symptoms suggestive of anorectal fistula or abscess so the diarrhoea is non-inflammatory most probably. Type 1 diabetes, hyperthyroidism, other metabolic causes of diarrhoea, malabsorption, adult celiac disease?

Characterisation of diarrhoea.

  • Watery diarrhea – The water content of chronic diarrhea can be caused by secretory or osmotic processes, or a combination of the two. Measure fecal electrolytes, pH, reducing substances and calculate the osmotic gap.
  • Secretory diarrhoea occurs in cholera and carcinoid. It is large in volume and persists on fasting.
  • Osmotic – Osmotic (or “substrate-induced” or “diet-related” or overeating) diarrhea typically is less voluminous than secretory diarrhea (eg, <200 mL per day), and improves or resolves during 12- to 24-hours of fasting. The presence of reducing substances or low fecal pH (ie, pH <6) suggest carbohydrate malabsorption.
  • Fatty diarrhea – Malabsorption is often accompanied by steatorrhea and the passage of bulky malodorous pale stools.
  • Inflammatory diarrhea – Inflammatory forms of diarrhea typically present with liquid loose stools with blood. Elevation in fecal calprotectin (a protein found in neutrophil granulocytes) indicates an inflammatory diarrhea.

You need to ask the appropriate questions to elicit this information even if you have noticed the goitre in your observation.

She has no symptoms suggestive of diabetes like polyuria, polydipsia and polyphagia but fewer than 30% have these symptoms so don’t rely on them. Check out her fasting blood sugar and HbA1c.

The problem is solved when you examine her. The pulse is 110/min, irregular; she is afebrile; BP is 110/70 mmHg; her thyroid is diffusely enlarged with no bruit or cystic feel to it; she has lidlag but no prominent proptosis and is not in heart failure nor does she have a valve lesion; there is a fine tremor in the outstretched hands. The diarrhoea is caused by hyperthyroidism.

The problems you will have to sort out and be asked about are

  • How to handle her AF; whether to anticoagulate or not; rate control or rhythm control; what rate to keep her pulse at.
  • What treatment is best for he to control her hyperthyroidism; pros and cons of propylthiouracil and its indications; how long to treat; use of beta blocker; when to prescribe radio iodine; what to do in pregnancy; teratogenic effects of the different drugs.
  • How to treat the diarrhoea.
  • How to treat the tremors.
  • How to get her weight up.
  • What is the pathophysiology behind the symptoms.
  • How to investigate her.
  • Interpretation of the tests.
  • What to do if she gets pregnant.
  • Diagnosis and treatment of a thyroid crisis.
  • How to treat proptosis.
  • What are the surgical options for Graves ophthalmopathy.
  • What is the response time and how to monitor the patient.
  • What is the relapse rate.

I will leave you to find out the answers and then you will be well prepared for a viva.

Evaluating chronic diarrhoea in an adult.

A 44-year-old man was evaluated at this hospital because of diarrhea, weight loss, and abdominal pain and irregular fever . Approximately 6 months before admission, the patient began to have early satiety, nausea approximately 30 minutes after eating small amounts of food, and intermittent anorexia. He began to consume primarily liquids, khichdi and sabudana for breakfast and lunch and would skip dinner; during the next 5 months, he lost 9 kg. His primary care physician gave him him metronidazole for five days to no avail.

Using metronidazole for chronic diarrhoea is a common mistake made in a third world country. It should not be used unless amoebiasis is confirmed. Watery diarrhoea is rarely associated with amoebiasis nor is fever. Amoebiasis may be asymptomatic or have may a subacute onset, usually over one to three weeks. Symptoms range from mild diarrhea to severe dysentery, producing abdominal pain (12 to 80 percent), diarrhea (94 to 100 percent), and bloody stools (94 to 100 percent), to fulminant amebic colitis. Rarely, acute fulminant necrotizing amebic colitis presents with life-threatening lower gastrointestinal bleeding without diarrhea. Weight loss occurs in about half of patients, and fever occurs in less than 38 percent. Mucus is present in stools.

The differential diagnosis of bloody diarrhea other than E. histolytica includes other causes of acute diarrhea or bloody stools, particularly bacterial pathogens including Shigella, Escherichia coli, Salmonella, Campylobacter, Clostridioides (formerly Clostridium) difficile, and some Vibrio species. Tools for the diagnosis of intestinal amebiasis include stool microscopy, stool antigen detection, stool polymerase chain reaction (PCR), serology, and colonoscopy with histologic examination. Metronidazole is used for amoebic dysentery and extra intestinal amoebic disease and (off the label) giardiasis and Crohn’s disease. It is used in H pylori eradication, anaerobic periodontal disease, skin infection and pneumonia and Cl difficile infection but not in acute watery diarrhoea. Using it in acute watery diarrhoea, chronic watery diarrhoea and suspected malabsorption is counterproductive and gives a poor impression in an examination candidate.

New, near-constant epigastric pain developed, approximately 1 hour after meals, nausea and vomiting occurred, with diffuse abdominal bloating and cramping. In addition, watery diarrhea began to occur twice daily, without hematochezia or melena. One week after discharge, the patient’s primary care physician prescribed omeprazole. The patient lost an additional 14 kg weight loss. The patient’s medical history was notable for depression, lumbar pain, and vitamin D deficiency. Intermittent diffuse headache persisted in the 3 weeks after discharge from the other hospital, and the patient reported low-grade fever. A review of systems was negative for night sweats, chills, neck pain, photophobia, vision changes, chest pain, dyspnea, cough, coryza,sore throat, oral ulcers, back pain, dysuria, hematuria, rashes, joint or muscle pain, edema, and pruritus. Medications included venlafaxine, cholecalciferol, and omeprazole. The patient took an herbal supplement of unknown type in the week after discharge from hospital. He had never used nonsteroidal antiinflammatory drugs. He had no known medication allergies. Approximately 3 weeks later, he presented to the emergency department of this hospital for evaluation again. He was dehydrated, the BP was 90/50 mmHg there was anemia, glossitis, angular stomatitis and cheilitis, he looked emaciated and had mild edema. His eyes were prominent, the thyroid was not enlarged. He had mild tremors in his hands. The lymph nodes were not enlarged.

Have these symptoms got any relationship to his medication? PPI use is associated with an increased risk of C. difficile infection, even in the absence of antibiotic use. Associations with other enteric infections, including salmonellosis and campylobacteriosis, have also been reported. However, the pathophysiologic mechanism involved in the increased risk of infection is unclear. PPI use has been associated with microscopic colitis, including lymphocytic and collagenous colitis. Cl difficile infection causes mild to severe bloody diarrhoea usually in people taking antibiotics such as fluoroquinolones, clindamycin, cephalosporins, and penicillins, though virtually any antibiotic can predispose to CDI. Do not use omeprazole indiscriminately in chronic diarrhoea unless you have a specific diagnosis in mind and then monitor the patient carefully.

How much importance should you give in your diagnostic evaluation to the tremor, prominent eyes, weight loss when the thyroid is not enlarged? Hyperthyroidism may present as diarrhoea but the other symptoms can be explained on the weight loss from the malabsorption caused by his chronic diarrhoeal illness. TSH at least needs to be checked but don’t base your whole diagnosis on hyperthyroidism.

The patient was discharged after IV fluids, oral rehydration salts, ciprofloxacin, and sucralfate and dicyclomine were given orally. and a diet of rice, yogurt, bland vegetables, chicken broth and lentils was advised. Wheat and gluten was avoided in the diet. Oral vitamin B complex and vitamin D were also given. 3 weeks after discharge the patient reported low-grade fever. A review of systems was negative for night sweats, chills, neck pain, photophobia, chest pain, dyspnea, cough, coryza, sore throat, oral ulcers, back pain, dysuria, hematuria, rashes, joint or muscle pain or pruritus. The patient was admitted to hospital again. Diarrhea and abdominal pain persisted on the second hospital day.

Tests for human immunodeficiency virus (HIV) type 1 and type 2 antibodies and antigen, Treponema pallidum antibodies, Clostridium difficile antigen, and tissue transglutaminase IgA were negative. Blood testing for Helicobacter pylori IgG was positive; however, a stool test for H. pylori antigen was negative.

This 44-year-old man presentswith a subacute gastrointestinal illness that is
characterized by epigastric pain, vomiting, diarrhea, and progressive weight loss during a 6-month period, Laboratory findings are notable for marked hypoalbuminemia, elevated levels of inflammatory markers, an elevated fecal calprotectin level, and a fluctuating absolute eosinophil count that approaches the threshold for eosinophilia (1500 cells), A CT abdomen showed air and fluid filled loops of the intestine with loss of folds in the duodenum and loss of haustrations in the colon, engorged mesenteric vessels and an enlarged mesenteric lymph node,

This patient lives in a slum in Karachi, with overcrowding, and his income is below the poverty line. Infection specially with Mycobacterium tuberculosis, bovis and avium must be considered and excluded. HIV testing must be repeated as M. avium may be a cause of diarrhoea associated with AIDs. Intestinal tuberculosis occurs in the absence of pulmonary infection or symptoms as milk and food nay be the source of the infection.

Whipple’s disease must be ruled out in this case. Whipple’s disease may be manifested by a subacute wasting illness. Infection with Tropheryma whipplei leads to infiltration of foamy macrophages into the small bowel, which results in a syndrome of abdominal pain, diarrhea, and malabsorption that is typically accompanied by joint pain. Other extraintestinal features include fever,
lymphadenopathy, and central nervous system abnormalities, such as dementia, cerebellar ataxia, and in rare cases, oculomasticatory myorhythmia. The diagnosis of Whipple’s disease can be made by periodic acid–Schiff staining of a small-bowel biopsy specimen, which would show foamy macrophages in the lamina propria of the gut.

Cancer must be included in the differential diagnosis, a malignant process seems unlikely, given the diffuse nature of the intestinal abnormality seen on CT imaging; nevertheless, consider the possibility of lymphoma. The gastrointestinal tract is the most common extranodal site of lymphoma. small-bowel lymphoma accounts for most cases. This patient has evidence of H. pylori infection,which may contribute to lymphoma involving the mucosa-associated lymphoid tissue of the stomach. The Mediterranean variety of small-bowel lymphoma, known as immunoproliferative small intestinal disease, may be manifested by abdominal pain, diarrhea, malabsorption, and weight loss. The other small-bowel lymphomas
include enteropathy-associated T-cell lymphoma (associated with celiac disease), Burkitt’s lymphoma, and B-cell lymphomas other than immunoproliferative small intestinal disease.

Autoimmune Disease
Celiac disease, which can cause a subacute syndrome of diarrhea and weight loss as well as hypoalbuminemia and evidence of mucosal hyperemia on imaging, is a consideration in this case. This patient had a negative tissue transglutaminase IgA test, but the total IgA level is not reported. When considering celiac disease, it is
important to first rule out concomitant IgA deficiency.

Autoimmune enteropathy is a rare disorder that can lead to subacute diarrhea and weight loss. It is characterized by a lymphocytic immune reaction that causes enterocyte destruction and intestinal villous blunting that can mimic severe celiac disease.

Strongyloides is a very unlikely possibility as the part of the world this patient lives in does not expose him to the proximity of pigs and swine hence this parasite which is common elsewhere as in African and Caribbean countries, is unlikely to have invaded him.

With the information provided here there is ample material for a good discussion.

A young woman with anemia: enough to fail a candidate.

An eighteen year old woman was brought to the hospital after a syncopal attack. She had fainted after carrying a heavy load of washed clothes in the morning. She was dizzy but conscious on reaching the hospital 2 hours later. She had recovered in a few minutes after falling to the ground, had not had any convulsive movements and had not hit her head on falling. She reported no diarrhea, loss of appetite, headache, jaundice, fever or muscle aches and pains. She had vomiting soon after meals, this has started 2 months ago and the vomitus contained recently eaten food. She lived in a slum area in Karachi with a widowed mother and two young brothers. The family lived below the poverty line. She was unmarried and had had her usual monthly menstruation. On examination her major finding was anemia.

She was asked by the candidate who was taking the history, whether she ate meat in her diet. She replied “When I can get it”,

“But can you eat it”

“Yes I can eat it”.

The right question should have been “Can your family afford to eat meat, chicken daal every day , once a week or only once or twice a month?”. The family lived off chapati, rice and leafy vegetables like herbs mostly so there was a strong element of malnutrition in the history. This was missed because of a sloppy history. Dietary history is usually skimped over in the ward rounds and when the dietary history is taken it is not interpreted nor used to help in the management or planning the treatment.

The next line of questioning was “Is your room clean and airy?”. As there is no evidence of respiratory symptoms or even fever this line of questioning seems irrelevant. Her family lived in a one room apartment with a toilet and lean-too kitchen in a crowded part of the city. Granted that you have been asked to look into the patient’s social circumstances but common sense is always permitted. Perhaps more information about previous episodes of loss of consciousness might have been more useful. Also asking if she had any food for breakfast might have helped. More information about the vomiting is more appropriate.

She had been in the hospital for three days before being brought to the examination room as a subject for a clinical examination. The patient had been transfused three units of blood (one a day for three days). The candidate asked about any blood transfusions, received the right answer but failed to pay attention to the patient’s answer and failed to mention it in the presentation. The candidate could not say why the patient had needed the blood transfusions. She had not bled and she had not had hemolysis nor did she have any bleeding tendency like purpura. She had a hemoglobin of 3.6 gm/dl on admission. The anemia was iron deficiency with microcytosis, low MCHC, low serum iron and low transferrin saturation and low serum ferritin.

The patient was not breathless, weighed 42 kg for a height of 5 ft 2 inches. She had a pulse of 102/min. BP of 100/58 mmHg, temperature of 98 F. She was pale, had koilonychia, had no jaundice. There small rubbery mobile lymph nodes in her neck on both sides. The size was 1 to 3 cm. Her JVP was not raised, her thyroid was not enlarged, her joints were normal and she had no rash or edema. She had no cardiomegaly but there was a systolic murmur in the aortic area but it did not radiate to the neck. She had a palpable spleen about 5 cm and it was firm. The liver was not enlarged, there was no ascites. The lungs were clear. There was no evidence of polyneuropathy, nor any change in the motor power or the reflexes.

How are you putting it all together? This means investigations and treatment.

Why is she iron deficient?

  • Lack of availability in the diet.
  • Hookworm infestation.
  • Iron malabsorption. Some foods interfere with iron malabsorption: tannates, phosphates, phytates (mineral-binding compounds found in whole grains and seeds), and foods high in calcium.
  • Celiac disease can contribute to anemia by several mechanisms, including iron deficiency, reduced absorption of supplemental iron, and malabsorption of other nutrients required for red blood cell (RBC) production including vitamin B12, folic acid, and copper. Anemia may be the only manifestation.
  • Autoimmune gastritis and H. pylori – Gastritis related to an autoimmune mechanism (eg, anti-parietal cell antibodies) or H. pylori has also been implicated in causing iron deficiency.
  • Urinary loss of iron. Chronic or intermittent intravascular hemolysis with hemosiderin accumulation in urinary epithelial cells may lead to iron loss through urinary shedding of these cells. Examples include individuals with intensive athletic training, prosthetic heart valve-associated hemolysis, or paroxysmal nocturnal hemoglobinuria (PNH).
  • Pulmonary hemosiderosis, such as in individuals with diffuse alveolar hemorrhage or idiopathic pulmonary hemosiderosis may lead to iron loss through swallowing of iron-laden alveolar or bronchial epithelial cells. These conditions also may cause a component of functional iron deficiency, in which iron is trapped in pulmonary macrophages.
  • Rare inherited disorders/IRIDAIRIDA due to TMPRSS6 mutation. Iron refractory iron deficiency anemia (IRIDA) is a rare inherited disorder in which absorption of oral iron is markedly impaired. IRIDA is caused by loss-of-function mutations of the TMPRSS6/matriptase 2 gene, which encodes a serine protease that cleaves membrane-bound hemojuvelin.
  • Extreme athletics. Iron deficiency may be seen in some athletes, due to gastrointestinal bleeding or reduced iron intake

Where is iron stored in the body?

  • Hemoglobin in circulating RBCs – Approximately 2 g, corresponding to approximately 2000 mL (25 to 30 mL/kg) of RBCs
  • Iron-containing proteins (eg, myoglobin, cytochromes, catalase) – Approximately 400 mg
  • Plasma iron bound to transferrin – 3 to 7 mg
  • Storage iron in the form of ferritin or hemosiderin – Approximately 0.8 to 1 g (men); approximately 0.4 to 0.5 g (women)

Ferritin levels are used as a surrogate for iron stores and are generally a good measure of storage iron as long as the individual does not have an active inflammatory process or chronic disease (ferritin is an acute phase reactant). For ferritin levels in the range from 20 to 300 ng/mL, there appears to be a direct quantitative relationship between the ferritin concentration and iron stores.

Stages of iron deficiency.

  1. iron deficiency but no anemia.
  2. anemia but it is normocytic and normochromic but with no increase in retic count.
  3. profound deficiency results in the classical findings of anemia with RBCs that are hypochromic (low mean corpuscular hemoglobin [MCH]) and microcytic (low mean corpuscular volume [MCV]). Reticulocyte production cannot be increased in the setting of iron deficiency, and the reticulocyte count becomes inappropriately low (despite being in the “normal” range in many cases).

Measuring iron deficiency anemia.

  • Low levels of ferritin and serum iron (Fe).
  • Increased levels of transferrin (Tf; total iron binding capacity [TIBC]). If only transferrin concentrations are available, they can be converted to the TIBC (in mcg/dL) by multiplying the transferrin concentration (in mg/dL) by 1.389.
  • Low percent saturation of transferrin (ie, Fe/TIBC or Fe/Tf, stated as a percent).
  • Increased unsaturated iron binding capacity (UIBC = TIBC – Fe).

What is this girl likely to have?

  1. Absolute iron deficiency – Absolute iron deficiency refers to the absence of (or severely reduced) storage iron in the monocyte-macrophage system, including bone marrow, liver, and spleen.
  2. Functional iron deficiency (also referred to as iron-restricted erythropoiesis) – Some individuals have barely adequate iron stores for normal hematopoiesis, but the iron is not available for RBC production. There are two main categories/mechanisms:
  3. Anemia of chronic inflammation – The most common mechanism is a block in iron release from macrophages back into the circulation, which occurs in the setting of inflammation and increased hepcidin production (ie, anemia of chronic inflammation, also called anemia of chronic disease [ACD]). Common causes include infections, malignancies, bariatric surgery (in certain individuals), or chronic medical conditions such as diabetes.

What is this patient likely to have?

  1. Disseminated TB. Despite the lack of pulmonary symptoms it is possible for her to pick up M tuberculosis from an open case in her neighborhood. She is malnourished and so is more then usually vulnerable. Lymph nodes and an enlarged spleen are found in disseminated TB. If an X ray chest shows miliary shadows the diagnosis can be confirmed further.
  2. Lymphoma affecting her pylorus. GI lymphomas are rare but should be ruled out as she has enlarged lymph nodes and an enlarged spleen.
  3. The iron deficiency is a confounding factor.
  4. Malnutrition needs to be addressed and treated. Iron refractoriness will remain until the inflammation subsides.

This patient was investigated and her iron deficiency was confirmed. She had no abnormal cells or blast cells in her blood film. The platelets are normal. The leucocyte count is unremarkable and the reticulocyte was 3%. The X ray was unremarkable with no hilar lymphadenopathy. An ultrasound of the abdomen showed a normal liver, confirmed the enlarged spleen and showed no evidence of any abdominal lymph nodes. A CT of the abdomen showed thickening of wall of the pyloric end of the stomach. A lymph node biopsy showed only reactive changes. It was decided to do an endoscopy and a biopsy was taken from the pyloric end of the stomach where cerebroid thickening of the mucosa was seen. Multiple biopsies were taken from the esophagus and other sites in the stomach and duodenum.

What was the consultant suspecting? The vomiting probably had an adverse effect on the anemia. The vomiting may be mechanical i.e. some obstruction in the area of the pylorus. She is not at the age (60 years) when lymphomas are seen in the stomach and also the wrong gender. Does anybody remember MALT?

How to assess gangrene in the toes. Looking for peripheral vascular disease.

A 56 year old man reports to the OPD with pain in his left fore foot and says that his toes are turning black. His left foot is swollen, with patches of red and blue skin, a non-healing ulcer on the dorsum and left side of the ankle with blue/black discoloration of the big toe which is beginning to shrivel, as well as discoloration of the second and third toes. A quick look at the other foot shows that small patches of blue discoloration are starting on the toes of the right foot too. This started about 6 weeks ago and has been progressive. You are in the short case section of a post graduate exam. What three questions will you ask to clarify a diagnosis?

  • Do you smoke and are you a current smoker?
  • Have you had pain on walking and is this pain starting at shorter distances now?
  • Do you suffer from diabetes?

What is likely to be causing this disease? The patient seems to have gangrene and non-healing ulcers caused by ischaemia of the foot. So why is the blood supply to the foot reducing to the point that it can no longer maintain the viability of the tissue? Peripheral arterial disease (PAD) is most often caused by arteriosclerosis.


How do you assess the risk in the population for PAD? The risk is higher in:

  • Male gender more than female gender.
  • Black ethnicity.
  • Age above 70 years.
  • With diabetes onset will be earlier.
  • Smokers, specially current smokers , the risk is higher and occurs in younger people.
  • Presence of coronary artery disease.
  • Hypertension is strongly associated with the development of atherosclerosis in men and women.
  • CKD makes the risk higher
  • A family history especially if associated with familial hyperlipidemia.
  • A history of intermittent claudication.
  • Abnormal pulses in the lower extremity.

The risk of PAD is increased in families identified with early-onset atherosclerosis, but no single genetic marker has been identified for PAD in this population.

Smoking . Cigarette smoking correlates significantly with cardiovascular disease. The mechanism by which cigarette smoke promotes the development and progression of atherosclerosis is not clearly understood, but its effects include endothelial damage, arterial smooth muscle proliferation, thrombophilia, inflammation, increased sympathetic tone, and other metabolic abnormalities. The NHANES study: the risk for PAD was increased in active cigarette smokers, but no association was found for other forms of tobacco exposure like gutka. paan, naswar but these were probably not studied in detail. In the Edinburgh Artery Study, smoking appears to be a more powerful risk factor for PAD than for CAD. Passive exposure to smoke appears to increase vascular endothelial inflammation and may increase the risk for atherosclerotic plaque development in children and adults.

Hypertension: Among those with an abnormal ankle-brachial index, the prevalence of hypertension in the Rotterdam Study was 60 percent. The NHANES study found that hypertensive patients also have an even higher prevalence of asymptomatic PAD. Hypertension together with smoking is a major factor for progression of PAD in patients with diabetes mellitus, but there is no evidence that adequate control of hypertension impacts disease progression.

Diabetes also increased the risk for developing symptomatic PAD (OR 2.6) in the Framingham Heart Study, which followed subjects for 38 years. The effect of diabetes on graft patency has varied between studies, with the majority finding no difference in patency rates but retrospective studies showed that the amputation rates are higher in diabetes.

Chronic kidney disease. Many guidelines do not specifically identify chronic kidney disease (CKD) as a risk factor for PAD. However, an association between PAD and CKD is being recognized and reported with increasing frequency.

Metabolic syndrome (a constellation of obesity, hypercholesterolemia, hypertension, and insulin resistance) is associated with increased risk for cardiovascular disease.

Hyperlipidemia. Patients with certain lipid and lipoprotein abnormalities [eg, total cholesterol, low-density lipoprotein (LDL) cholesterol, triglycerides, lipoprotein (a)] have an increased risk for cardiovascular disease, and adverse long-term. cardiovascular outcomes.

Homocysteine was one of the earliest biomarkers to be studied in association with the development of atherosclerosis. Elevated homocysteine is associated with earlier-onset atherosclerosis and is present in up to 40 percent of patients with PAD.

Heavy metals: arsenic, lead, cadmium have been linked to coronary artery disease and PAD. Arsenic is found in sparklingly clear drinking water (ask for symptoms of abdominal pain, vomiting diarrhoea and hair loss) and is associated with high homocysteine levels in blood. In a review using data from the NHANES, after adjusting for known risk factors, comparing the highest with lowest quartiles, the risk for PAD trended higher for cadmium and for lead.

What is the area of distribution or pattern of arterial disease?

  • Type I: The coronary arterial bed. Because of the prevalence of CAD many risk factors such as diabetes and hyperlipidemia are considered CAD equivalents. PAD is regarded as a coronary heart disease risk equivalent.
  • Type II: The major branches of the aortic arch (eg, carotid, subclavian).
  • Type III: The visceral arterial branches of the abdominal aorta.
  • Type IV: The abdominal aorta and lower extremity arteries.
  • Type V: A combination of two or more of these categories occurring simultaneously.

Is there a difference in the progression of disease in in the different arterial beds? More rapid progression of disease occurred most frequently in those with aortic arch branch disease and visceral artery disease. Gender did not influence the rate of progression; however, the risk for recurrence or progression of disease in the same category and in a new category was significantly greater in younger patients. In most other studies evaluating the natural progression of disease of the aorta and lower extremities, symptoms tend to remain stable . Patients who continue to smoke cigarettes and those with diabetes mellitus are generally at the highest risk for progression of disease.

What are the risks in early onset of PAD?

Early-onset atherosclerosis, or premature atherosclerosis, is defined as PAD presenting prior to 50 years of age. Patients with early-onset atherosclerosis are more frequently male, are active smokers, have diabetes, and more often present with critical limb ischemia. A defect in coagulation or fibrinolysis is identified in up to 75 percent of patients with early-onset atherosclerosis. In one study, 30 percent had hypercoagulable states, and 47 percent had platelet aggregation defects.

This patient was not a diabetic. His blood pressure was 130/75 mmHg and he had never been treated for hypertension. He was lean and thin and had never had angina or a heart attack. He needs to be asked about transient ischaemic attacks. He is 56 so should be investigated for coagulation defects. He had been a smoker in his youth but had not smoked for 10 years.

The clinical manifestations of PAD (claudication, rest pain, ulceration, and gangrene) are predominantly due to progressive luminal narrowing (stenosis/occlusion), although thrombosis or embolism of unstable atherosclerotic plaque or thrombotic material can also occur.

What tissue diagnosis will you make for this patient?

Chronic limb-threatening ischemia (CLTI) is the clinical syndrome, defined by the presence of PAD in combination with rest pain, gangrene, or a lower limb ulceration >2 weeks duration, which fits this patient best. The nature of the clinical manifestations depends upon the time course over which arterial narrowing or occlusion occurs; this in turn affects the extent to which the collateral circulation can develop. Acute-on-chronic reductions in limb perfusion, which may be due to atheroembolism, cholesterol embolism, or thrombotic occlusion of a stenotic vessel, cause diffuse limb pain. Chronic severe reduction in limb perfusion is present as ischemic rest pain, typically localized to the forefoot and toes, and as tissue loss (nonhealing ulcer, gangrene) are also present.

How are you going to assess this patient?

  • Check the peripheral pulses.
  • Measure the an ankle-brachial index (ABI) ≤0.9. The ABI is a comparison of the resting systolic blood pressure at the ankle to the higher systolic brachial pressure.
  • Duplex ultrasonography is commonly used in conjunction with the ABI to identify the location and severity of arterial obstruction.
  • Advanced vascular imaging (computed tomographic [CT] angiography,
  • Magnetic resonance [MR] angiography,
  • Catheter-based arteriography) is usually reserved for patients in whom there remains uncertainty following noninvasive testing, or in whom intervention is anticipated.

Medical management consists of cessation of smoking, reduction in weight in obese patients. Does not apply to this patient. Control of diabetes and hypertension. Measure serum lipids and modify them with dietary measures and statins and antiplatelet therapy. Consider aspirin, clopidogrel, ticagrelor, vorapaxar. Read up the PEGASUS-TIMI, the CAPRI and EUCLID trials.

Claudication is managed with supervised exercising, the addition of the phosphodiesterase inhibitor, cilostazol, may also improve symptoms. Statin therapy may also improve pain-free walking time in patients with claudication, but the evidence for this is conflicting. There is no evidence that beta blocker therapy for treatment of high blood pressure worsens claudication.

Ischemic rest pain or tissue loss. Once a patient develops ischemic rest pain or tissue loss, the natural history often involves a persistent decline and an increased risk of major limb amputation unless there is some form of intervention to improve arterial perfusion. This patient will need forefoot amputation after waiting to see where the ischaemia line develops. For this patient:

  • As this patient has wet gangrene/ abscess ulcers, the wound should be debrided or drained immediately regardless of the anticipated need for revascularization.
  • Use of antibiotics.
  • The wound should be lightly wrapped with a bulky dry gauze bandage, avoiding excess pressure that could aggravate ischemia. Following revascularization, the wound should be monitored closely for signs of healing, or for tissue necrosis/drainage that may indicate a need for further debridement.
  • Once the decision has been made to intervene, a three-step integrated approach (PLAN) is suggested that includes Patient risk estimation, Limb staging using WIfI and determining the ANatomic pattern of disease using the Global Anatomic Staging System (GLASS).

Concern over paclitaxel. Following percutaneous intervention, a number of medical therapies aimed at preventing restenosis, but only local delivery of the drug paclitaxel has been shown to improve the longevity of interventions for lower extremity PAD. However, the overall safety of paclitaxel-coated balloons and stents placed into the legs of patients with PAD has come into question.

I have tried to put in all the points where you can be assessed or a point put forward for discussion or your opinion can be sought. Please read up the trials mentioned and many others which clinicians use to improve the management of their patients.

Young women with mitral valve disease, atrial fibrillation or not and heart failure. What will be discussed in the viva voce examination.

Scenario 1.

A 16 year old girl is brought by her family to a tertiary care cardiac facility for management. She has been unwell for 5 years with severe palpitation, breathlessness which is exertional, recurrent swelling of the face and feet and has needed hospitalisation for worsening of her symptoms, to the local hospitals near the village where she lives. Her family have been told that that she has a cardiac valve disease in which the valve is tight and leaky and that she needs surgery for it’s correction. She comes from a poor family and until now they have decided against her surgery. Her brothers are now working so the family decided to come to the city for her surgery as their financial circumstances now permit them to afford a stay in the city. You assess her for further management.

These are the problems that you see:

  • She is in heart failure. She is severely breathless, tachypnea and orthopneic; prefers to sit up. Her feet and face are swollen, she has some ascites, a raised JVP, bibasilar creps, an enlarged liver which is pulsatile. Her praecordium is bulging and very pulsatile. The apex beat is in the anterior axillary line. This indicates that the cardiomegaly has been there for some years pushing out the sternum.
  • The pulmonary hypertension may be irreversible making the prognosis poor.
  • The pulse is rapid 104/min at rest and irregular. BP is 100/65 mm Hg. She is fibrillating and has lost the 25% boost that a contracting atrium give to the diastolic pulse. She may throw an embolus.
  • Cardiac auscultation shows variable intensity of the first heart sound, a pansystolic murmur all over the precordium, with a loud second pulmonary sound and an irregular heart beat. She has a mitral valve which cannot close properly so is incompetent, causing blood to regurgitate back into the left atrium when the left ventricle contracts. She has pulmonary hypertension indicating that the mitral valve was/is stenosed as well and she is fibrillating. As her liver is enlarged and pulsatile and the regurgitant murmur is prominent over the tricuspid, there is tricuspid regurgitation which is probably functional.

What problems will you look for if you are evaluating her for possible valve replacement surgery?

  • Has she got active carditis? You are going to be asked how you will evaluate her for carditis so be prepared.
  • Has she got a clot in her left atrium and does she need anticoagulation? Is anticoagulation likely to reduce her risk of embolisation even if she does not have a clot? These points will be discussed so know the answer.
  • Can her AF be converted to sinus rhythm or can she be managed by rate control?
  • Does she have an enlarged left atrial appendage? Is removal of an enlarged left atrial appendage likely to reduce the incidence of AF post operatively?
  • What therapy does she need to improve her cardiac status and ejection fraction and tricuspid regurgitation? Remember that ACE-I are not useful in valvular heart disease.
  • Is her pulmonary hypertension reversible or fixed?
  • Does she have bacterial endocarditis and vegetations? How will you assess her for endocarditis?
  • What is the status of her aortic valves?
  • Which prosthetic valves are suitable for valvular replacement in this patient?
  • Will she be able to have a baby once she has her new valve? How do you manage a pregnancy in a patient with a valvular heart disease?

When you assess her you have to keep these points in mind. You will definitely need to keep these points in mind when planning her management as well as for counselling her about her prognosis.

Scenario 2.

A 27-year-old primigravid woman at 25 weeks 5 days of gestation presented to the emergency department in respiratory distress. She had been well until the evening before, when a cough productive of blood-tinged, frothy sputum had developed and worsened progressively. She noted shortness of breath and chest pain but no fevers, chills, hemoptysis, lower-extremity edema, or calf pain. She reported regular fetal movement and no uterine contractions.

  • What is the significance of calf pain? Pregnancy is a hypercoagulable state so think of deep vein thrombosis in the legs.
  • Why is she breathless? The cause may be similar to a non-pregnant woman which may include community-acquired pneumonia, asthma exacerbation, pulmonary embolism, and cardiogenic or noncardiogenic pulmonary edema.
  • Look for cardiovascular causes of pulmonary edema in pregnancy which include preeclampsia with severe asymptomatic hypertension or hypertensive emergency, valvular heart disease, and cardiomyopathy.
  • Peripartum cardiomyopathy would not be expected at this stage of pregnancy, nor would amniotic-fluid embolism.
  • Why is it necessary to ask about uterine contractions? Chorioamnionitis-induced acute respiratory distress syndrome is rare in the absence of premature labor or ruptured membranes.

This patient comes from the Indian subcontinent. The incidence of rheumatic heart disease is still common. She may give a history of sore throat, or fever associated with swollen painful joints but 25% have no history and at least 25% have forgotten. Ask if she had to take monthly injections as prophylaxis which she is more likely to remember. Also ask if she has had episodes of palpitation or breathlessness in the past.

She was in acute respiratory distress and sitting up; she was coughing and using accessory muscles of ventilation. The temperature was 37.4°C, the pulse 144 beats per minute and regular, the blood pressure 142/80 mm Hg, and the respiratory rate 30 breaths per minute. The oxygen saturation was 76% while the patient was breathing ambient air and increased to 85% with the use of a nonrebreather face mask delivering 70% oxygen. The jugular venous pressure was elevated to the angle of the jaw. Chest examination revealed diffuse rales bilaterally. Cardiac examination revealed tachycardia with a left parasternal lift and a prominent pulmonic component of the second heart sound (P2); no murmurs were detected. The abdomen was normal. The fundal height was 23 cm. The fetal heart rate was 130 to 140 beats per minute. The cervix was closed. The extremities were warm, pedal pulses were 2+ bilaterally, and there was no edema.

The ECG showed sinus rhythm and P mitrale. This indicates an enlarged left atrium.

An ultrasound of the abdomen was deferred because of he respiratory distress.

Urgent bedside echocardiography showed changes consistent with rheumatic mitral-valve disease with predominant stenosis, chordal thickening, restricted leaflet motion, and a “hockey stick” appearance of the anterior leaflet. The mean mitral-valve pressure gradient was 20 mm Hg at a heart rate of 140 beats per minute. Mitral regurgitation was qualitatively mild. The left atrium was severely enlarged (volume index, 80.74 ml per square meter). The systolic pressure in the pulmonary artery was markedly elevated (95 mm Hg). Right ventricular hypertrophy and signs of pressure overload were present. The size and thickness of the left ventricle were normal, as was systolic function.

The findings are consistent with severe rheumatic mitral stenosis, complicated by advanced pulmonary hypertension and right ventricular pressure overload.

This is her Xray chest.

Her primary care physician after blood, urine, and sputum cultures had been obtained, administered intravenous furosemide, methylprednisolone, vancomycin, and ceftazidime and transferred her to a tertiary care institution for further management of her condition. Why was she given steroids? What is the use of antibiotics? Why steroids?

The findings are consistent with severe rheumatic mitral stenosis, complicated by advanced pulmonary hypertension and right ventricular pressure overload. In pregnancy, even low degrees of mitral stenosis can be associated with increased maternal and fetal morbidity and mortality, because the dilutional anemia and decreased plasma oncotic pressure of pregnancy may promote pulmonary edema at lower hydrostatic pressures.

What are the triggers which have set off the pulmonary edema and increased the pulmonary hypertension?

  • Hypervolemia of pregnancy.
  • Increased circulation from the pregnant uterus.
  • Reduction in vital capacity from an enlarging uterus.
  • Dilutional anemia of pregnancy.
  • Decreased plasma oncotic pressure in pregnancy

In the majority of pregnant women with symptomatic severe mitral stenosis, heart-rate control and judicious diuretic administration restore hemodynamic stability. When these measures failed, valve intervention was considered. Percutaneous balloon mitral valvuloplasty is the preferred intervention and was performed in this patient.

What kind of delivery be planned in severe or even moderate mitral stenosis?

Vaginal delivery with epidural anesthesia is usually recommended; a cesarean section is performed for obstetrical indications and in patients with the most precarious hemodynamic status. The Valsalva maneuver may be poorly tolerated, because it transiently decreases preload and causes compensatory tachycardia. The second stage of labor should therefore be shortened when possible. The stress of the Valsalva maneuver may be alleviated by allowing the fetal head to passively move downward during the second stage of labor, reducing the amount of time spent pushing. If there is hemodynamic instability, delivery may be assisted with the use of forceps or vacuum extraction. Most patients do not require invasive hemodynamic monitoring during delivery.

So pregnancy is not only possible with valve disease, the valve lesion is usually detected after the pregnancy has been established as the hemodynamic changes in pregnancy set off heart failure.

Scenario 3.

A 32 year old woman was admitted in a tertiary care hospital with gross enlargement of her abdomen, had pain on the right side of the abdomen for the last 10 days. She was severely breathless so that she had difficulty in talking so was able to give only a brief history, coughed up frothy sputum, could not lie flat on her bed, had swollen feet. When her distress was relieved by giving IV diuretic, oxygen and opioid injection she gave the history that she had been unable to do any housework for the past 3 months with her 12 year old daughter doing the cooking and cleaning. with a neighbour coming in to look after her toilet needs. Sha had had 3 pregnancies and her youngest child was 11 months old. At each pregnancy she became severely breathless and bedridden. She had not been able to come to a hospital for an antenatal examination and her pregnancy and deliveries had been managed by the village midwife. All three had been vaginal deliveries.

She had gross ascites, was not jaundiced, her liver was enlarged by 9 centimeters below the costal margin and her spleen was 6 cm and firm in consistency. She had no markers of chronic liver disease. Her pulse was 120/min, regular, BP was 90/60 mmHg, respiratory rate was 30/min, she was afebrile. Her JVP was markedly raised, there was edema up to mid thighs, her precordium was hyperdynamic with a palpable systolic thrill all over the precordium, the cardiac apex was in the midclavicular line on the left side. The first heart sound was soft, with a pansystolic murmur almost drowning the both heart sound but in the pulmonary area P2 could be heard quite distinctly. There was no early diastolic or mid diastolic murmur or an opening snap. There were marked crepitations all over the chest with evidence of bilateral pleural effusion.

What is unusual about her presentation and findings? She is obviously in advanced heart failure hut why is the fluid retention localising to her peritoneal cavity, why is the liver painful and tender and what is the significance of the enlarged spleen?

What is the difference between a firm spleen and a soft spleen? A soft spleen has recently been enlarged so can occur in fevers such as endocarditis, typhoid fever, recent onset malaria, brucellosis etc. A firm spleen has been there for weeks or months so think of chronic conditions like portal hypertension, disseminated TB, chronic leukemia, lymphoma etc.

The liver is painful because of recent and sudden onset of enlargement of the liver. Possible rapid decompensation of the valvular heart disease has caused TR and the liver size has gone up suddenly. The spleen indicates that the portal pressure is rising and is being transmitted via the portal vein the portal system. The patient may have early onset of cardiac cirrhosis not just congestive cardiomegaly. She has no fever but has endocarditis damaged the valve further caused more pressure on th right or left ventricle causing further decompensation?

As you can see that each patient has something subtly different because the disease is progressing differently. You have to sort out which problem is more important in every patient. You have to remember that you are not treating a valve lesion but a valve lesion which is causing different difficulties in different people so each patient needs an assessment that takes into all the different factors.

I have given you plenty of points for thought. The candidates who are not able to discuss these points are not going to survive in a post graduate assessment.

Corona Viruses 2019, why the mutation and what can be done.

The 2019-nCoV corona virus identified in the current outbreak in the Wuhan province in China is the third virus which has mutated from animals to infect human beings. This one has been traced to a seafood market in Wuhan province. The two other pathogenic human respiratory coronaviruses are : severe acute respiratory syndrome coronavirus [SARS-CoV] and Middle East respiratory syndrome coronavirus [MERS-CoV]. As of January 24, 2020, there were more than 800 reported cases of 2019-nCoV, with a mortality rate of 3%. The viral genome has been sequenced, and these results show that it is 75 to 80% identical to the SARS-CoV and even more closely related to several bat coronaviruses. How is this going to help? Reverse transcriptase polymerase chain reaction assays can be developed for early detection in human beings before symptoms begin and in the wet markets where the spread began initially. Hence we can detect how widespread the infection is. Vaccines can be developed.

How do these viruses spread and do they all spread in the same way? Transmission of SARS-CoV and MERS-CoV occurred to a large extent by means of superspreading events. These superspreading events are diseases which occur at the same time as the virus invades the patient: the virus then uses the same pathways as the concomitant illness, in the case of SARS-CoV and 2019-CoV lower respiratory illnesses so the infection appears along with the other lower respiratory disease. SARS-CoV mutated over the 2002–2004 epidemic to better bind to its cellular receptor and to optimize replication in human cells, enhancing virulence. The frequent mutations occur because of error prone RNA-dependent RNA polymerases. MERS-CoV does not appear to mutate in this fashion. It is likely that 2019-nCoV will behave more like SARS-CoV and further adapt to the human host, with enhanced binding to hACE2. It will be necessary to study the virus at different geographical locations as well as in autopsy samples to determine the degree of mutation and virulence.

A key question is identification of the zoonotic origin of the virus. It has close similarity to bat coronaviruses, so it is likely that bats are the primary reservoir for the virus. SARS-CoV was transmitted to humans from exotic animals in wet markets, whereas MERS-CoV is transmitted from camels to humans. In both cases, the ancestral hosts were probably bats. Whether 2019-nCoV is transmitted directly from bats or by means of intermediate hosts is important to understand and will help define zoonotic transmission patterns. Fruit bats are apart of far-eastern cuisine as are other exotic animals.

Do masks help in the prevention of 2019-CoV? The paper masks being use probably do not prevent the virus from emerging from the nose into the environment but do prevent people from touching their mouths and noses, and help prevent the virus from spreading to surfaces like tables, desks etc. The best prevention is washing hands and wiping all work surfaces with an antiseptic.

If we are lowering cholesterol (LDL) how low should it go to effectively achieve an effect?

The current guidelines of the American Heart Association and the American Stroke Association (AHA–ASA) recommend “intense” statin therapy after an ischemic stroke of atherosclerotic origin but do not stipulate a target level of LDL cholesterol because there are limited data on outcomes with different targets for LDL cholesterol. Most physicians prescribe high-intensity statin therapy after stroke, however the prescription is usually changed to a low or moderate statin dose thus only a moderate reduction in the level of LDL cholesterol is achieved. In a multicenter, multinational registry (TIAregistry.org) that enrolled patients with TIA or minor ischemic stroke who were followed in TIA clinics during a 5-year period, 70% of the patients had been prescribed a statin at the time of hospital discharge, only 63% were still taking a statin at 5 years. Among these patients, the mean (±SD) LDL cholesterol level went from 119±41 mg per deciliter (3.1±1.1 mmol per liter) at baseline to 92±32 mg per deciliter (2.4±0.8 mmol per liter) at 5 years. What was the clinical benefit achieved?

Intensive therapy to lower serum lipid levels with the use of statins is recommended after transient ischemic attack (TIA) or ischemic stroke of atherosclerotic origin. These recommendations are based on the results of the Stroke Prevention by Aggressive Reduction in Cholesterol Level (SPARCL) trial that showed a 16% lower incidence of recurrent stroke with atorvastatin (at a dose of 80 mg per day) than with placebo in patients with stroke and no known coronary heart disease. In the group with carotid stenosis, there was a 33% lower incidence of stroke in the atorvastatin group than in the placebo group. A subsequent analysis of the data from that trial showed that patients who reached a level of low-density lipoprotein (LDL) cholesterol of less than 70 mg per deciliter (1.8 mmol per liter) had a 28% lower relative risk of stroke than those who reached a level of 100 mg per deciliter (2.6 mmol per liter). A meta-regression analysis, including results from the SPARCL trial, showed that the risk of stroke was 20% lower for every reduction of 39 mg per deciliter (1.0 mmol per liter) in the LDL cholesterol level, without any threshold effect. How did the authors do this? They used a statin and ezitamibe in both groups but changed the dosage to achieve a target of an LDL level of 70 mg/dl or 90 mg/dl. both the cardiovascular and neurovascular progression of cholesterol related injury were targeted. The composite primary end point of major cardiovascular events included ischemic stroke, myocardial infarction, new symptoms leading to urgent coronary or carotid revascularization, or death from cardiovascular causes. 2860 patients were followed up for three and a half years, (the South Korean patients were followed up for a shorter period as they entered the trial late) . After an ischemic stroke or TIA with evidence of atherosclerosis, patients who had a target LDL cholesterol level of less than 70 mg per deciliter had a lower risk of subsequent cardiovascular events than those who had a target range of 90 mg to 110 mg per deciliter. (Funded by the French Ministry of Health and others; Treat Stroke to Target ClinicalTrials.gov number, NCT01252875).

What exactly are we looking at?

The trial was conducted in 61 sites in France and 16 sites in South Korea. The nutritional transition in South Korea despite its gains in its economy and a transition towards western culture has not seen an equivalent increase in the use of dairy products or an increase in dietary fat. Obesity is not at the level of the West.

The age of the patients was diverse 18 years (for Koreans 20 years) and up. Was there the same degree of atherosclerosis in younger patients or for the same genetic or dietary reason?

All patients had already had a neurological adverse event and had a stable neurological deficit. Most had cardiac disease as well. All imaging was performed when the responsible clinician determined that knowledge of intracranial steno-occlusive disease or severe aortic atheroma would alter treatment. The choice of cardiovascular tests and the diagnosis of atherosclerotic stenosis were made and judged by the investigators and were not standardized or adjudicated.

Too late to lock the barn door?

All patients were treated to maintain blood pressure at a target level of 130/80 mm Hg in those with diabetes: to less than 140/90 mm Hg in all others, to maintain a glycated hemoglobin level of less than 7%, and were encouraged to stop smoking. Were these the confounding factors?

At a median of 2.7 years in the two groups, discontinuation rates were 30.3% and 28.5%, respectively.

there was a numerically higher number of intracranial hemorrhages in the lower-target group than in the higher-target group, in the SPARCL trial, than in the Heart Protection Study, but the 95% confidence interval for the hazard ratio suggested that the between-group difference was not significant in this trial. In addition, in the SPARCL trial, incident diabetes was 30% higher in the group assigned to receive atorvastatin (80 mg per day) than in the placebo group.

So what do we learn? Those with carotid artery stenosis were the ones who benefitted as their incidence of a recurrence was less when the cholesterol was lowered to 70 mg/dl. Those who already had cardio-atheroma disease also tended to do better with the lower LDL cholesterol. However the patients with the lower LDL cholesterol tended to have a higher incidence of intracranial hemorrhage. should the LDL be lowered to 50 mg/dl. What should be done about the diet? Is this low a LDL cholesterol sustainable? Let us think about that.


A Comparison of Two LDL Cholesterol Targets after Ischemic Stroke
List of authors.
Pierre Amarenco, M.D., Jong S. Kim, M.D., Julien Labreuche, B.S.T., Hugo Charles, B.S.T., Jérémie Abtan, M.D., Yannick Béjot, M.D., Lucie Cabrejo, M.D., Jae-Kwan Cha, M.D., Grégory Ducrocq, M.D., Ph.D., Maurice Giroud, M.D., Celine Guidoux, M.D., Cristina Hobeanu, M.D., et al., for the Treat Stroke to Target Investigators*

January 2, 2020
N Engl J Med 2020; 382:9-19
DOI: 10.1056/NEJMoa1910355