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Rheumatology Primary Care Chapter

Specialty Topic Author Status Resident Survival Guide Author Status
Rheumatology Gout Needs content Gout resident survival guide Needs content
Rheumatology Systemic lupus erythematosus Seems complete - need review SLE resident survival guide Iqra, Aditya Needs fixing
Rheumatology Temporal arteritis Seems complete - need review Temporal arteritis resident survival guide WE DONT NEED IT
Rheumatology Synovial fluid aspiration and analysis
Rheumatology Kawasaki's disease Seems complete - need review Kawasaki disease resident survival guide
Rheumatology Rheumatoid arthritis Seems complete - need review Rheumatoid arthritis resident survival guide
Rheumatology Osteoarthritis Seems complete - need review
Rheumatology Septic arthritis Seems complete - need review Septic arthritis resident survival guide Iqra, Aditya Needs review
Rheumatology Vasculitis Seems complete - need review Vasculitis resident survival guide
Rheumatology Antiphospholipid syndrome Seems complete - need review Antiphospholipid syndrome resident survival guide Needs content
Rheumatology Osteoporosis Seems complete - need review Osteoporosis resident survival guide Eiman Complete
Rheumatology Fibromyalgia Seems complete - need review Fibromyalgia resident survival guide
Rheumatology Monoarthritis Seems complete - need review - add algorithm
Rheumatology Polyarthritis Seems complete - need review - add algorithm
Rheumatology Joint pain ??? Joint pain resident survival guide Dr MARS Needs content


Emergency Medicine Chapters - Internal Medicine Related
Specialty Intended Chapter - Available Chapter Responsible Fellow / Leader Chapter Status Resident Survival Guide Responsible Fellow / Leader Chapter Status
Emergency Medicine Shock - Shock
Emergency Medicine Sepsis - Sepsis Sepsis resident survival guide Ahmed Complete
Emergency Medicine Coma and Altered Mental Status - Coma Altered mental status resident survival guide Moises Main chapter needs content
Emergency Medicine Anaphylaxis and allergies - Anaphylaxis Anaphylaxis resident survival guide
Emergency Medicine Delirium - Delirium (?) Delirium resident survival guide Complete (?)
Emergency Medicine Sedation and analgesia - Sedation / Analgesic
Emergency Medicine Pain Management - Pain
Emergency Medicine Airway Management - Intubation Mechanical ventilation Mechanical ventilation resident survival guide
Emergency Medicine Cardiac Arrest - Sudden cardiac death#Cardiac Arrest as a Subtype of Sudden Death
Emergency Medicine CPR - Cardiopulmonary resuscitation Amir Bagheri
Emergency Medicine Acute Respiratory Insufficiency - Respiratory failure
Emergency Medicine Fever - Fever Fever of unknown origin resident survival guide Gerry Complete
Emergency Medicine Hypothermia - Hypothermia
Dyspnea - Dyspnea / Shortness of breath Not assigned Shortness of breath resident survival guide

Dyspnea resident survival guide

Steven

Eiman

Needs review
Chest Pain - Chest pain Aisha Adigun Chest pain resident survival guide Rim/Alejandro In progress
Syncope - Syncope Not assigned Syncope resident survival guide Karol/Alejandro
Nausea and Vomiting - Nausea and vomiting
Cough Cough resident survival guide Sara Haddadi In progress
Hemoptysis - Hemoptysis Hemoptysis resident survival guide Teresa Complete
Acute Diarrhea - Diarrhea Gastroentritis survival guide Needs review
Jaundice - Jaundice
Abdominal Pain - Abdominal pain
Headache - Headache Headache resident survival guide Niloofar In progress
Ascitis - Ascites
Lumbar Pain - Low back pain
CARDIOLOGY EMERGENCIES
Cardiology STEMI - ST elevation myocardial infarction STEMI resident survival guide Alejandro Complete
Cardiology NSTEMI - Unstable angina / non ST elevation myocardial infarction Unstable angina/ NSTEMI resident survival guide Yaz Complete
Cardiology Atrial Fibrillation - Atrial fibrillation Atrial fibrillation resident survival guide Vidit Complete
Cardiology Tachyarrhythmias - Tachyarrhythmia Wide complex tachycardia resident survival guide / where is narrow? Rim Complete
Cardiology Bradycardia - Bradycardia Ibtisam Ashraf Bradycardia resident survival guide Ogheneochuko: Vidit Complete
Cardiology Acute Heart Failure - Congestive heart failure Heart failure resident survival guide hmoud / Dr. Kaya Complete
Cardiology Hypertensive Emergencies - Hypertensive crisis Hypertensive crisis resident survival guide Ayokunle Complete
Cardiology Acute Aortic Syndromes - Aortic dissection / Aortic aneurysm Aortic dissection resident survival guide / Thoracic aortic aneurysm resident survival guide / Abdominal aortic aneurysm resident survival guide Chetan/Serge / Rghaye Marandi

Arash Moosavi

Complete
Cardiology Acute Pericarditis - Pericarditis Pericarditis resident survival guide Mugilan
Cardiology Cardiac Tamponade - Cardiac tamponade Cardiac tamponade resident survival guide Ayokunle
Cardiology Acute Myocarditis - Myocarditis Homa Myocarditis
Cardiology Infectious Endocarditis - Endocarditis Endocarditis resident survival guide Mohamed
Hematology Deep Vein Thrombosis - Deep vein thrombosis
Hematology Acute Arterial Occlusion - Thromboembolism - VTE Syed Hassan A. Kazmi Complete VTE prevention resident survival guide Needs review
PULMONOLOGY EMERGENCIES
Pulmonology Asthma - Asthma - Asthma exacerbation Asthma exacerbation resident survival guide Abdurahman, Vidit Complete
Pulmonology CPOD - Chronic obstructive pulmonary disease COPD exacerbation resident survival guide Complete
Pulmonology Community-acquired Pneumonia - Pneumonia Alejandro Needs review Community acquired pneumonia resident survival guide Rim / Chetan Complete
Pulmonology Pulmonary Abscess - Lung abscess
Pulmonology Pneumonitis - Pneumonitis
Pulmonology Alveolar Hemorrhage - Pulmonary hemorrhage
Pulmonology Pleural Effusion - Pleural effusion Pleural effusion resident survival guide Twinkle Complete
Pulmonology Pulmonary Thromboembolism - Pulmonary embolism Pulmonary embolism resident survival guide Rim
Pulmonology Pneumothorax - Pneumothorax
Pulmonology Upper Airway Infections - Sinusitis / Sore throat / Ear pain Sinusitis resident survival guide

Sore throat resident survival guide

Ear pain resident survival guide

Moises

Mydah

...

INFECTIOUS DISEASES EMERGENCIES
Infectious Diseases HIV - Human Immunodeficiency Virus (HIV) Needs review HIV resident survival guide (?) (?)
Infectious Diseases Influenza - Influenza Influnza resident survival guide Mounika In progress
Infectious Diseases Urinary Tract Infections - Urinary tract infection Needs review Urinary tract infection resident survival guide Ogheneochuko Complete
Infectious Diseases Dengue Fever - Dengue fever
Infectious Diseases Leptospirosis - Leptospirosis
Infectious Diseases Rocky Mountain Spotted Fever - Rocky Mountain spotted fever
Infectious Diseases Typhus - Typhus
Infectious Diseases Hemorrhagic Fever - Viral hemorrhagic fever
Infectious Diseases Tetanus - Tetanus
Infectious Diseases Chikungunya - Chikungunya
Infectious Diseases Zika Virus Disease - Zika virus infection
Infectious Diseases Yellow Fever - Yellow fever
Infectious Diseases Ebola - Ebola
NEUROLOGIC EMERGENCIES
Neurology Stroke - Stroke
Neurology Subarachnoid Hemorrhage - Subarachnoid hemorrhage
Neurology Subdural Hemorrhage Fahime
Neurology Intraparenquimatous Intracranial Hemorrhage Intraparenchymal hemorrhage Ahmad NOT MICROCHAPTER
Neurology CNS Infections - Encephalitis / Meningitis Meningitis resident survival guide Niloofar


NOT MICROCHAPTER STRUCTURE

In progress

Neurology Acute Flaccid Paralysis - Flaccid paralysis NOT MICROCHAPTER STRUCTURE
Neurology Seizures - Seizure Needs content Seizure resident survival guide / Epilepsy resident survival guide Vidit - epilepsy not assigned Complete
Neurology Vertigo - Vertigo Needs content Dizziness resident survival guide Moises Complete
GI EMERGENCIES
Gastroenterology Hepatic Encephalopathy - Hepatic encephalopathy
Gastroenterology Hepatorenal Syndrome - Hepatorenal syndrome
Gastroenterology Upper Digestive Hemorrhage - Upper gastrointestinal bleeding
Gastroenterology Lower Digestive Hemorrhage - Lower gastrointestinal bleeding
Gastroenterology Spontaneous Bacterial Peritonitis - Spontaneous bacterial peritonitis
Gastroenterology Secondary Peritonitis - Secondary peritonitis
Gastroenterology Hepatic Failure - Hepatic failure
Gastroenterology Hepatitis - Hepatitis Hepatitis survival guide Needs review
Gastroenterology Acute Diverticulitis - Diverticulitis
Gastroenterology Acute Pancreatitis - Acute pancreatitis
NEPHROLOGY EMERGENCIES
Nephrology Acute Renal Injury - Acute kidney injury Farima Acute kidney failure resident survival guide Kanwal
Nephrology Rhabdomyolisis - Rhabdomyolysis
Nephrology Acid-base Disorders - Acidosis / Alkalosis Acidosis resident survival guide

Alkalosis resident survival guide

NEEDS DIAGNOSTIC APPROACH

NEEDS CONTENT

Nephrology Hyponatremia - Hyponatremia Needs content Hyponatremia resident survival guide Pryamvada Complete
Nephrology Hypernateremia - Hypernatremia Feham Tariq Hypernatremia resident survival guide Mounika Complete
Nephrology Hypokalemia - Hypokalemia Zorkum Needs content Hypokalemia resident survival guide
Nephrology Hyperkalemia - Hyperkalemia Singh Hyperkalemia resident survival guide Complete
Nephrology Hypocalcemia - Hypocalcemia Kaur Hypocalcemia resident survival guide Ammu ---
Nephrology Hypercalcemia - Hypercalcemia
Nephrology Nephrolithiasis - Nephrolithiasis Singh Nephrolithiasis resident survival guide Complete
ENDOCRINOLOGY EMERGENCIES
Endocrinology Hypoglycemia - Hypoglycemia Medhat ?
Endocrinology Hyperglycemias - Hyperglycemia DKA HONK/HHS Hassan / Hussnain Complete
Endocrinology Thyreotoxic Crisis - Thyroid storm
Endocrinology Mixedema Coma - Myxedema coma Aditya Complete
Endocrinology Adrenal Insufficiency - Adrenal insufficiency Ayeesh.K In progress
RHEUMATOLOGY EMERGENCIES
Rheumatology Acute Monoarthritis - Monoarthritis
Rheumatology Vasculitis - Vasculitis / Behçet's Behçet's disease / Antiphospholipid Syndrome Antiphospholipid syndrome / Sclerodermic Renal Crisis / Erythema Nodosum Erythema nodosum Sclerodermic renal crisis not AVAILABLE
Rheumatology Septic Arthritis - Septic arthritis
Rheumatology Gout - Gout THERE IS NO LEADER ON RHEUMATOLOGY - NOR RESIDENT SURVIVAL GUIDES ON ITS MAIN PAGE
HEMATOLOGY EMERGENCIES
Hematology Coagulhopaties -Coagulopathy Needs reworking
Hematology Bleeding - Bleeding Sogand Goudarzi Needs content Bleeding disorder resident survival guide Needs content
Hematology Sickle Cell Disease - Sickle-cell disease
Hematology Febrile Neutropenia - Febrile neutropenia Febrile neutropenia resident survival guide Rim Complete
Hematology Acute Transfusional Reactions - Transfusion reaction
Hematology Thrombocytopenia - Thrombocytopenia Farbod Zahedi Tajrishi Needs content Thrombocytopenia resident survival guide Ogheneochuko Complete
Hematology DIC - DIC Omer Kamal Needs review DIC resident survival guide Ogheneochuko Complete
Hematology Pancytopenia - Pancytopenia Zorkum Needs review Pancytopenia resident survival guide Needs review
Hematology Oncologic Emergencies - Tumor Lysis Syndrome - Tumor lysis syndrome
GENERAL EMERGENCIES
Emergency Medicine Exogenous Intoxications - Intoxication Needs reworking
Emergency Medicine Drowning - Drowning
Emergency Medicine Alcohol Withdraw Syndrome - Alcohol withdrawal
Emergency Medicine Poisonous Animals-related Accidents Not available
Emergency Medicine Opioid Overdose - Opioid overdose Opioid overdose resident survival guide Complete (?)
Emergency Medicine Carbon Monoxide Poisoning - Carbon monoxide poisoning Carbon monoxide poisoning resident survival guide
Emergency Medicine Burns - Burns
Emergency Medicine Frostbite - Frostbite
Emergency Medicine Altitude Sickness - Altitude sickness
Emergency Medicine Food Poisoning - Food poisoning
DERMATOLOGY EMERGENCIES
Dermatology Pharmacodermias - Stevens-Johnson syndrome / Toxic epidermal necrolysis
Dermatology Acute Dermatosis -

Herpes-Zoster Herpes zoster;

Erysipela Erysipelas;

Cellulitis Cellulitis;

Necrotizing Fasciitis Necrotizing fasciitis;

Antrax Anthrax;

Furuncullosis Boil;

Contact Dermatitis Contact dermatitis;

Atopic Dermatitis; Atopic dermatitis

(...)

NO LEADER ON DERM - NO CHAPTER LIST
Dermatology Urticaria Urticaria and Angioedema Angioedema Angioedema resident survival guide Needs reviewing
OBGYN EMERGENCIES
Gynecology Gynecologic Emergencies -

Vaginitis Vaginitis:

-Bacterial Vaginosis Bacterial vaginosis;

-Candida Vulvovaginitis Candida vulvovaginitis;

-Trichomoniasis Trichomoniasis;

-Genital Herpes Herpes simplex;

-Contact Vaginitis;

-Atrophic Vaginitis Atrophic vaginitis;

Cervicitis Cervicitis

Bartholin Cyst Bartholin's cyst and Abscess;

Vaginal Foreign Objects; Foreign bodies#Foreign bodies in humans

Vulvar Trauma;

Acute Pelvic Inflammatory Disease; Pelvic inflammatory disease

Vaginal Bleeding; Vaginal bleeding

Sexual Violence, Rape

Ovary Torsion Ovarian torsion

Vulvovaginitis resident survival guide missing!!!

No other chapter here listed on OB/GYN page

Bartholin's not available - abscess

Foreign bodies not available

Vulvar trauma not available

Sexual Violence may need REWORK

Obstetrics Obstetric Emergencies:

Preterm labor and birth; Preterm labor and birth

Breech birth; Breech birth

Dystocias; Dystocia

Chord Prolapse; Umbilical cord prolapse

Rupture of Membranes: Rupture of membranes

Hypertensive Pregnancy Disease (Eclampsia and Preeclampsia); Eclampsia Pre-eclampsia

Placenta previa; Placenta previa

Placental Abruption; Placental abruption

Abortion;

Trauma;

Obstetrical hemorrhage - Obstetrical hemorrhage

NO RESIDENT SURVIVAL GUIDE CREATED

ALL CHAPTERS NEED CONTENT

Abortion not available

Preterm not available

Dystocia not available

Classification not available on Eclampsia

OPHTHALMOLOGY EMERGENCIES
Ophthalmology Ophthalmologic Emergencies:

Chemical Burn;

Ocular Perforation - Penetrating Trauma;

Palpebral Laceration;

Orbital Hemorrhage;

Preseptal Cellulitis; Periorbital cellulitis

Post septal Cellulitis; Periorbital cellulitis

Dacryocystitis; Dacryocystitis

Orbital Fractures; Blowout fracture

Acute Glaucoma; Glaucoma

Endophthalmitis; Endophthalmitis

Hyposphagmia (subconjunctival hemorrhage);

Viral Conjunctivitis; Conjunctivitis

Neonatal Conjunctivitis;

Red eye - Red eye

NO LEADER/ NO RESIDENT SURVIVAL GUIDE


Red eye resident survival guide

Red eye - Arash Moosavi Periorbital Cellulits

Endophthalmitis and Glaucoma not on microchapters

Intraocular hemorrhage not accurately depicting intraocular hemorrhage

Others not present

ENT EMERGENCIES
ENT Otorrhinolaryngologic Emergencies:

Airway Obstruction - Airway obstruction

Vocal Chord Paralysis - Vocal cord paresis

Laryngeal Trauma -

Amigdalitis/Pharyngitis - Pharyngitis

Peritonsillar abscess - Peritonsillar abscess

Foreign bodies

Epistaxis - Epistaxis

Facial Fractures - Maxillofacial trauma / LeFort fracture / Nasal bone fracture / Nasal fracture

Rhinosinusitis - Rhinosinusitis

Otitis - Otitis

Peritonsillar abscess - Prince Djan

Retropharyngeal abscess - Vishal Devarakonda

Deep neck infection - Gerry

Otitis externa - Tarek

Otitis media - needs content

Rhinitis - needs content

Otitis interna - needs content

Rhinosinusitis

needs content-

NO RESIDENT SURVIVAL GUIDE Amigdalitis - not present

Pharyngitis - needs removing definition


SURGICAL EMERGENCIES
Surgery Politrauma - Polytrauma
Psychiatry PSYCHIATRIC EMERGENCIES
Pediatrics PEDIATRIC EMERGENCIES
Orthopedics ORTHOPEDIC EMERGENCIES


Editor-In-Chief: C. Michael Gibson, M.S., M.D. [3]; Associate Editor(s)-in-Chief: José Eduardo Riceto Loyola Junior, M.D.[4]

Overview

Heartburn is the feeling of burning or pressure inside the chest, normally located behind the breastbone, which can last for several hours and may worsen after food ingestion. Some patients may also have a peculiar acid taste in the back of the throat accompanied with excessive salivation, regurgitating gas and bloating.[1] The most common cause of heartburn is gastroesophageal reflux disease (GERD), in which the lower esophageal sphincter allows for gastric content to reflux into the esophagus. This may cause atypical symptoms which includes: coughing, wheezing or asthma-like symptoms, hoarseness, sore throat, dental erosions or gum disease, discomfort in the ears and nose. Heartburn is a symptom though, and it can have other causes besides GERD, such as esophagitis (infections, eosinophilic) and esophageal cancer. It can also be mistaken by chest pain and presented in life-threatening diseases such as acute coronary syndromes, aortic dissection and pericarditis.

Causes

Life Threatening Causes

Heartburn can be expressed by the patient as a type of chest pain. While evaluating heartburn, it is mandatory to differentiate it from cardiac chest pain.

Life-threatening causes include conditions that may result in death or permanent disability within 24 hours if left untreated.

Differentiating heartburn from angina [2] [3]
Heartburn (GERD) Angina or Heart Attack
Burning chest pain, begins at the breastbone Tightness, pressure, squeezing, stabbing or dull pain, most often in the center
Pain that radiates towards the throat Pain radiates to the shoulders, neck or arms
Sensation of food coming back to the mouth Irregular or rapid heartbeat
Acid taste in the back of the throat Cold sweat or clammy skin
Pain worsens when patient lie down or bend over Lightheadedness, weakness, dizziness, nausea, indigestion or vomiting
Appears after large or spicy meal Shortness of breath
Symptoms appears with physical exertion or extreme stress

Common Causes

Diagnosis

Below is shown a compendium of information summarizing the diagnosis of gastroesophageal reflux disease (GERD) according the the American Journal of Gastroenterology guidelines.[4]

The diagnosis of GERD is made based on:

  • Symptom presentation;
  • Response to antisecretory therapy;
  • Objective testing with endoscopy;
  • Ambulatory reflux monitoring.[4]


 
 
 
Classic symptoms of GERD
(heartburn and regurgitation)
 
If there are warning signs*:
upper endoscopy during the initial evaluation
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PPI 8-week trial
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
If better: GERD probable
 
If refractory, proceed to refractory GERD algorithm


* Dysphagia, bleeding, anemia, weight loss and recurrent vomiting are considered warning signs and should be investigated with upper endoscopy.


Shown below is an algorithm summarizing the treatment of refractory GERD according the the American Journal of Gastroenterology guidelines.[4]

 
 
 
 
 
 
Treat GERD:
Start a 8-week course of PPI
 
If there are warning signs*:
upper endoscopy during the initial evaluation
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Refractory GERD
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Optimize PPI therapy
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
No response:
Exclude other etiologies
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Typical symptoms:
Upper endoscopy
 
 
 
 
 
Atypical symptoms:
Referral to ENT, pulmonary, allergy
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Abnormal:
(eosinophilic esophagitis, erosive esophagitis, other)
Specific treatment
 
NORMAL
 
Abnormal:
(ENT, pulmonary, or allergic disorder)
Specific treatment
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
REFLUX MONITORING
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Low pre test probability of GERD
 
High pre test probability of GERD
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Test off medication with pH or impedance-pH
 
Test on medication with impedance-pH
 
 
 
 

Perform upper endoscopy to detect esophageal adenocarcinoma and Barret’s esophagus. Surveillance examinations should occur not more frequently than once every 3 to 5 years. If the patient presents with Barret's esophagus or dysplasia, more frequent intervals are indicated. [5]

Screening for H. Pylori is not recommended routinely on GERD. [5]

Diagnostic Testing for GERD [4] [6]
Test Indication Recommendation
Proton Pump Inhibitor (PPI) trial Classic symptoms, no warning/alarm symptoms If negative does not rule out GERD
Barium swallow Use for evaluating dysphagia Only useful for complications (stricture, ring)
Endoscopy Use if alarm symptoms, chest pain or high risk* patients Consider early for elderly, high risk for Barret’s, non-cardiac chest pain, patients unresponsive to PPI
Esophageal biopsy Exclude non-GERD causes
Esophageal manometry Pre operative evaluation for surgery Rule out achalasia/scleroderma-like esophagus pre-op
Ambulatory reflux monitoring Preoperatively for non-erosive disease, refractory GERD symptoms or GERD diagnosis in question Correlate symptoms with reflux, document abnormal acid exposure or reflux frequency

Treatment

Shown below is an algorithm summarizing the treatment of refractory GERD according the the American Journal of Gastroenterology guidelines.[4]

Lifestyle modifications are indicated for all patients and include:

  • Dietary changes (reduce ingestion of chocolate, caffeine, alcohol, acidic and/or spicy foods - low degree of evidence, but there are reports of improvements with elimination);
  • Weight loss for overweight patients or patients that have had recent weight gain;
  • Head of bed elevation and avoidance of meals 2–3 h before bedtime if nocturnal symptoms.[4]
Medications used in GERD
Medication Indication Recommendation
PPI therapy All patients without contraindications Use the lowest effective dose, safe during pregnancy
H2-receptor antagonist May be used as a complement to PPIs or as maintenance option in patients without erosive disease Beware tachyphylaxis after several weeks of usage
Prokinetic therapy and/or baclofen Used if symptoms do not improve Undergo diagnostic evaluation first
Sucralfate Pregnant women No role in non-pregnant patients


Do's

  • Differentiate heartburn from cardiac chest pain;
  • Consider a twice daily dosing in patients with night-time symptoms, variable schedules, and/or sleep disturbance;
  • Advise the patient to cease eating chocolate, caffeine, spicy foods, citrus or carbonated beverages;
  • Strongly recommend weight loss if patient's BMI is >25 or recent weight gain;
  • Recommend head of bed elevation if nocturnal GERD;
  • Advise against late evening meals;
  • Promote alcohol and tobacco cessation.
  • If there is an alarm symptom such as dysphagia
  • If there's no response with such measures and initial 8-week PPI treatment, refer patient to a specialist.

Don'ts

  • Do not request an upper endoscopy for every patient complaining of GERD;
  • Do not request manometry or ambulatory reflux monitoring routinely.

References

  1. "Gastro-oesophageal reflux disease and dyspepsia in adults: investigation and management". National Institute for Health and Care Excellence: Clinical Guidelines. 2019. PMID 31935049.
  2. "Heartburn vs. heart attack - Harvard Health".
  3. Bösner S, Haasenritter J, Becker A, Hani MA, Keller H, Sönnichsen AC; et al. (2009). "Heartburn or angina? Differentiating gastrointestinal disease in primary care patients presenting with chest pain: a cross sectional diagnostic study". Int Arch Med. 2: 40. doi:10.1186/1755-7682-2-40. PMC 2799444. PMID 20003376.
  4. 4.0 4.1 4.2 4.3 4.4 4.5 4.6 Katz PO, Gerson LB, Vela MF (2013). "Guidelines for the diagnosis and management of gastroesophageal reflux disease". Am J Gastroenterol. 108 (3): 308–28, quiz 329. doi:10.1038/ajg.2012.444. PMID 23419381.
  5. 5.0 5.1 "www.worldgastroenterology.org" (PDF).
  6. Moayyedi P, Lacy BE, Andrews CN, Enns RA, Howden CW, Vakil N (2017). "ACG and CAG Clinical Guideline: Management of Dyspepsia". Am J Gastroenterol. 112 (7): 988–1013. doi:10.1038/ajg.2017.154. PMID 28631728.


Template:WikiDoc Sources


CLAUDICATION

Overview

Claudication is the description of cramping muscle pain that occurs after a certain degree of exercise and is relieved by rest. Claudication is classically caused by peripheral arterial disease, in which an obstruction in artery of the lower limbs can lead to an insufficient blood flow which is not enough to supply the demands from the muscles of that region, but there are other conditions that can mimic its symptoms such as nerve root compression, spinal stenosis, hip arthritis, symptomatic Baker's cyst, venous claudication and chronic compartment syndrome.

Causes

Life Threatening Causes

There are no life-threatening causes, which include conditions which may result in death or permanent disability within 24 hours if left untreated.

Common Causes

Diagnosis

Shown below is a flowchart for diagnostic testing for suspected peripheral arterial disease according to the 2016 AHA/ACC guidelines:

 
 
 
 
 
 
 
 
 
Suspected PAD
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Symptoms:
Leg pain at rest
❑ Reduced or absent pulses
Leg pain during exertion
Gangrene
❑ Pale extremity
❑ Non healing wound
Calf or foot cramping
Paresthesias
 
 
Suspected critical limb ischemia
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Order Ankle brachial index
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
≤ 0.90
 
 
 
 
Normal
1.00-1.40
Borderline
0.91-0.99
 
 
 
 
 
 
 
> 1.40
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Order Exercise ankle-brachial index if exertion non-joint related leg symptoms
If absent - search for alternative diagnosis
 
 
 
 
 
 
 
Order Toe-Brachial Index
 
Exercise ankle-brachial index
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Does the patient have > 20% decrease in Postexercise ABI?
 
 
 
 
 
 
 
Is TBI < 0.7?
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Yes
 
 
No
 
 
No
 
 
Yes
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PAD confirmed
 
 
 
 
 
No PAD - search for alternative diagnosis
 
 
 
 
PAD confirmed
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Lifestyle-limited claudication despite guideline-directed management and therapy, revascularization considered
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Yes
 
 
 
 
 
 
No?
Continue guideline-directed management and therapy
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Anatomic assessment: (Class I)
❑ Duplex ultrasound
❑ Computed tomography angiography
❑ Magnetic resonance angiography
 
 
 
Anatomic assessment: (Class IIa)
❑ Invasive angiography
 
 
 
 
 
 
 
 
 
 
 
 


Shown below is a table summarizing the differential diagnosis of claudication according the age and clinical presentation:

Differential Diagnosis of Intermittent Claudication and Lower Limb Pain
In younger patients:
Diagnosis Clinical Features Diagnostic Method of Choice Treatment
Buerger's Disease Rare vasculitis mostly seen in young Asians males who are smokers. Causes inflammation and thrombosis of the arteries of the legs, feet, forearms, and hands. Conventional angiography - multilevel occlusions and segmental narrowing of the lower extremity arteries with extensive collateral flow showing a corkscrew or “tree root” appearance Smoking cessation
Extrinsic Compression by Bone Lesions Not a common cause, 40% of osteochondromas arise from the posterior aspect of distal femur compressing the femoral artery. MRI, limb x-ray or CT scan Excision of the lesion and repair of the affected artery
Popliteal Artery Entrapment Syndrome Common in young patients with claudication, especially athletes - compression of the popliteal artery by the medial head of the gastrocnemius muscle. Stress angiography Surgery
Fibromuscular Dysplasia Affects young women of childbearing age, affects mostly renal, cerebral and visceral arteries but may affect limbs as well. Angiography - string-of-beads appearance Angioplasty
Takayasu's Arteritis Rare vasculitis mostly seen on Asian and South American women. Stenosis of the abdominal aorta and iliac arteries are present in 17% of the patients and may cause claudication. Conventional angiography Corticosteroids, methotrexate, azathioprine, and cyclophosphamide
Cystic Adventitial Disease 1 in 1200 cases of claudication, most common in men, 20-50 years without risk factors for atherosclerosis. It is caused by repetitive trauma, which causes the formation of a mucin-containing cystic structure in the wall of the popliteal artery. Conventional angiography, MRI Complete excision of the cyst with prosthetic and vein replacement, as well as bypass
In older patients:
Spinal Stenosis Motor weakness is the most important symptom, which may be accompanied by pain. It starts soon after standing up, and may be relieved by sitting or bending (lumbar spine flexion) MRI Analgesic drugs, physical therapy, acupuncture or surgery (gold standard)
Peripheral Arterial Disease May present with absent or reduced peripheral pulses, and audible bruits but some patients may not present with these symptoms. A low ankle-brachial pressure index (<0.9) is suggestive of the disease but if normal it does not exclude it. An exercise ankle-brachial pressure index can be done on patients that doesn't present with these signs.

Other clinical features include: decreased skin temperature, shiny, hairless skin over the lower extremities, pallor on elevation of the extremity, dystrophic toenails, and rubor when the limb is dependent.

Handheld Doppler, conventional angiography Smoking cessation, antiplatelet drugs, statins, diabetes and blood pressure control, exercise, percutaneous transluminal angioplasty.
Nerve Root Compression Caused by compression of the nerve root by other structure, such as an herniated disc. The pain usually radiates down the back of the leg and is described as sharp lancinating pain. It may be relieved by adjusting the position of the back (leaning forward). MRI Surgery
Hip Arthritis Pain starts when the patient undergoes weight bearing and is worsened by activity. The pain is continuous and intensified by weight bearing, with inflammatory signs such as tenderness, swelling, and hyperthermia. MRI Surgery
Baker's Cyst Pain is worsened with activity, not relieved by resting, and may have tenderness and swelling behind the knee. Ultrasound, MRI Surgery

Treatment

Shown below is an algorithm summarizing the diagnosis of claudication due to peripheral arterial disease according the the British Medical Journal guidelines.

 
 
 
 
 
Evaluate affected limb - check for color and trophic changes, early ulcerations, skin temperature, capillary refill time, pulses at the groin and popliteal fossa, and the pedal pulses.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
If peripheral arterial disease is suspected: Screening test: ankle-brachial index (systolic blood pressure of the dorsalis pedis, posterior tibialis, or fibularis artery is obtained with a handheld Doppler and divided by the higher of the two brachial pressures) - if <0.9 confirms peripheral arterial disease.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Secondary prevention for coronary arterial disease: start aspirin 75mg daily and statins
 
Control cardiovascular risk factors (hyperglycemia, obesity, dyslipidemia, smoking)
 
Advise the patient to exercise for 30 minutes twice daily to increase pain-free walking and total walking distance by stimulating collateral blood flow)
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cilostazol may be used for improving symptoms[1]
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Be aware of the 5 Ps—pain, pale, pulseless, paraesthesia, paralysis—indicating an acute limb ischemia
 
 
 

Do's

  • Assess for peripheral arterial disease, as it is the most common cause for intermittent claudication, but do consider other causes depending on the age;
  • Confirm the diagnosis by measuring the ankle-brachial pressure indices;
  • Assess the risk factors for atherosclerosis and control them. Encourage patients to cease smoking, to control the blood glucose, prescribe antiplatelet drugs, optimize antihypertensive medication doses, start statins and encourage exercise;
  • If there's no improvement, symptoms are disabling or diagnosis is uncertain, refer to a specialist.[2]
  • Best treatment options for peripheral arterial disease are: open surgery, endovascular therapy, and exercise therapy. These were superior to medical management in achieve higher walking distance and managing claudication.
  • Antiplatelet drugs with either aspirin or clopidogrel alone is recommended to reduce myocardial infarction, stroke, and vascular death in patients with symptomatic PAD.[3]
  • In patients with claudication, supervised exercise programs increases functional status and reduce leg symptoms.[3]
  • Patients with diabetes mellitus should be oriented to perform self-foot examination and healthy foot behaviors. Quick diagnosis and treatment of foot infections can prevent amputation.[3]

Don'ts

  • Symptomatic treatment of the claudication and leg pain must not overshadow the reduction of cardiovascular risk, as these patients have a significantly increased risk of death.
  • When treating peripheral arterial disease, always attempt reducing symptoms with less invasive treatment options such as exercising, do not immediately refer patients to more invasive treatment options;
  • Don't forget to address other causes of claudication if the patient is presenting it at a younger age, or if the treatment doesn't improve the symptoms.
  • Do not perform invasive or non-invasive anatomic assessments for asymptomatic patients.[3]
  • In patients not at increased risk of peripheral arterial disease, and without history of physical examination findings suggestive of PAD, the ankle-brachial index is not recommended.[3]
  • Anticoagulation should not be used to reduce the risk of cardiovascular ischemic events in patients with PAD.[3]
  • Pentoxifylline is not effective for treatment of claudication.[3]

References

  1. Carman TL, Fernandez BB (2000). "A primary care approach to the patient with claudication". Am Fam Physician. 61 (4): 1027–32, 1034. PMID 10706155.
  2. 3.0 3.1 3.2 3.3 3.4 3.5 3.6


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(...)

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [5]; Associate Editor(s)-in-Chief: José Eduardo Riceto Loyola Junior, M.D.[6]

Tocolytic agents according to the American College of Obstetricians and Gynecologists[1]
Agent or Class Maternal Side Effects Fetal or Newborn Adverse Effects Contraindications
Calcium channel blockers Dizziness, flushing, and hypotension; suppression of heart rate, contractility, and left ventricular systolic pressure when used with magnesium sulfate; and elevation of hepatic transaminases No known adverse effects Hypotension and preload-dependent cardiac lesions, such as aortic insufficiency
Nonsteroidal anti-inflammatory drugs Nausea, esophageal reflux, gastritis, and emesis; platelet dysfunction is rarely of clinical significance in patients without underlying bleeding disorder In utero constriction of ductus arteriosus*, oligohydramnios*, necrotizing enterocolitis in preterm newborns, and patent ductus arteriosus in newborn† Platelet dysfunction or bleeding disorder, hepatic dysfunction, gastrointestinal ulcerative disease, renal dysfunction, and asthma (in women with hypersensitivity to aspirin)
Beta-adrenergic receptor agonists Tachycardia, hypotension, tremor, palpitations, shortness of breath, chest discomfort, pulmonary edema, hypokalemia, and hyperglycemia Fetal tachycardia Tachycardia-sensitive maternal cardiac disease and poorly controlled diabetes mellitus
Magnesium sulfate Causes flushing, diaphoresis, nausea, loss of deep tendon reflexes, respiratory depression, and cardiac arrest; suppresses heart rate, contractility and left ventricular systolic pressure when used with calcium channel blockers; and produces neuromuscular blockade when used with calcium-channel blockers Neonatal depression Myasthenia gravis


Differentiating croup and epiglottitis[2][3]
Croup Epiglottitis
Clinical features Acute stridor with coughing and lack of drooling Acute stridor with drooling and lack of coughing
Course Slow-developing airway obstruction - rare severe obstruction Rapidly courses with complete airway obstruction and shock
Imaging Steeple sign in an anterior-posterior neck x-ray Thumb sign in a lateral neck x-ray
Additional clinical features

(less reliable for diagnostic)

Sore throat

Barking cough

Sore throat

Sitting position

Refusal of food or drink

Inability to swallow

Vomiting

Treatment Nebulization of racemic epinephrine:

Preferred regimen: 0.5 mL of a 2.25% racemic epinephrine solution diluted in 3 mL of normal saline

Invasive airway management (oral intubation or tracheotomy)

Antibiotics

Intensive care unit





Histologic criteria for the recognition and assessment of microscopic lesions related to gastroesophageal reflux disease (GERD) – the Esohisto project criteria[4]
Proliferative changes of the squamous epithelium Criterion Definition and method of assessment Severity score
Basal cell layer Hyperplasia Basal cell layer thickness in μm as a proportion (%) of total epithelial thickness (10×) 0 (<15%)

1 (15–30%)

2 (>30%)

Papillary Elongation Papillary length in μm as a proportion (%) of total epithelial thickness (10×) 0 (<50%)

1 (50–75%)

2 (>75%)

Dilated intercellular spaces Identify as irregular round dilations or diffuse widening of intercellular space (40×) 0 (absent)

1 (<1 lymphocyte)

2 (≥1 lymphocyte)

Inflammatory infiltrate Intraepithelial Eosinophils Count in the most affected high-power field (4×0) 0 (absent)

1 (1–2 cells)

2 (>2 cells)

Inflammatory infiltrate Intraepithelial Neutrophils Count in the most affected high-power field (40×) 0 (absent)

1 (1–2 cells)

2 (>2 cells)

Inflammatory infiltrate Intraepithelial mononuclear cells Count in the most affected high-power field (40×) 0 (0–9 cells)

1 (10–30 cells)

2 (>30 cells)


Overview

Heartburn is the feeling of burning or pressure inside the chest, normally located behind the breastbone, which can last for several hours and may worsen after food ingestion. Some patients may also have a peculiar acid taste in the back of the throat accompanied with excessive salivation, regurgitating gas and bloating.[5] The most common cause of heartburn is gastroesophageal reflux disease (GERD), in which the lower esophageal sphincter allows for gastric content to reflux into the esophagus. This may cause atypical symptoms which includes: coughing, wheezing or asthma-like symptoms, hoarseness, sore throat, dental erosions or gum disease, discomfort in the ears and nose. Heartburn is a symptom though, and it can have other causes besides GERD, such as esophagitis (infections, eosinophilic) and esophageal cancer. It can also be mistaken by chest pain and presented in life-threatening diseases such as acute coronary syndromes, aortic dissection and pericarditis.

Causes

Life Threatening Causes

Heartburn can be expressed by the patient as a type of chest pain. While evaluating heartburn, it is mandatory to differentiate it from cardiac chest pain.

Life-threatening causes include conditions that may result in death or permanent disability within 24 hours if left untreated.

Differentiating heartburn from angina [6] [7]
Heartburn (GERD) Angina or Heart Attack
Burning chest pain, begins at the breastbone Tightness, pressure, squeezing, stabbing or dull pain, most often in the center
Pain that radiates towards the throat Pain radiates to the shoulders, neck or arms
Sensation of food coming back to the mouth Irregular or rapid heartbeat
Acid taste in the back of the throat Cold sweat or clammy skin
Pain worsens when patient lie down or bend over Lightheadedness, weakness, dizziness, nausea, indigestion or vomiting
Appears after large or spicy meal Shortness of breath
Symptoms appears with physical exertion or extreme stress

Common Causes

Diagnosis

Below is shown a compendium of information summarizing the diagnosis of gastroesophageal reflux disease (GERD) according the the American Journal of Gastroenterology guidelines.[8]

The diagnosis of GERD is made based on:

  • Symptom presentation;
  • Response to antisecretory therapy;
  • Objective testing with endoscopy;
  • Ambulatory reflux monitoring.[8]


 
 
 
Classic symptoms of GERD
(heartburn and regurgitation)
 
If there are warning signs*:
upper endoscopy during the initial evaluation
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PPI 8-week trial
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
If better: GERD probable
 
If refractory, proceed to refractory GERD algorithm


* Dysphagia, bleeding, anemia, weight loss and recurrent vomiting are considered warning signs and should be investigated with upper endoscopy.


Shown below is an algorithm summarizing the treatment of refractory GERD according the the American Journal of Gastroenterology guidelines.[8]

 
 
 
 
 
 
Treat GERD:
Start a 8-week course of PPI
 
If there are warning signs*:
upper endoscopy during the initial evaluation
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Refractory GERD
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Optimize PPI therapy
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
No response:
Exclude other etiologies
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Typical symptoms:
Upper endoscopy
 
 
 
 
 
Atypical symptoms:
Referral to ENT, pulmonary, allergy
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Abnormal:
(eosinophilic esophagitis, erosive esophagitis, other)
Specific treatment
 
NORMAL
 
Abnormal:
(ENT, pulmonary, or allergic disorder)
Specific treatment
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
REFLUX MONITORING
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Low pre test probability of GERD
 
High pre test probability of GERD
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Test off medication with pH or impedance-pH
 
Test on medication with impedance-pH
 
 
 
 

Perform upper endoscopy to detect esophageal adenocarcinoma and Barret’s esophagus. Surveillance examinations should occur not more frequently than once every 3 to 5 years. If the patient presents with Barret's esophagus or dysplasia, more frequent intervals are indicated. [9]

Screening for H. Pylori is not recommended routinely on GERD. [9]

Diagnostic Testing for GERD [8] [10]
Test Indication Recommendation
Proton Pump Inhibitor (PPI) trial Classic symptoms, no warning/alarm symptoms If negative does not rule out GERD
Barium swallow Use for evaluating dysphagia Only useful for complications (stricture, ring)
Endoscopy Use if alarm symptoms, chest pain or high risk* patients Consider early for elderly, high risk for Barret’s, non-cardiac chest pain, patients unresponsive to PPI
Esophageal biopsy Exclude non-GERD causes
Esophageal manometry Pre operative evaluation for surgery Rule out achalasia/scleroderma-like esophagus pre-op
Ambulatory reflux monitoring Preoperatively for non-erosive disease, refractory GERD symptoms or GERD diagnosis in question Correlate symptoms with reflux, document abnormal acid exposure or reflux frequency

Treatment

Shown below is an algorithm summarizing the treatment of refractory GERD according the the American Journal of Gastroenterology guidelines.[8]

Lifestyle modifications are indicated for all patients and include:

  • Dietary changes (reduce ingestion of chocolate, caffeine, alcohol, acidic and/or spicy foods - low degree of evidence, but there are reports of improvements with elimination);
  • Weight loss for overweight patients or patients that have had recent weight gain;
  • Head of bed elevation and avoidance of meals 2–3 h before bedtime if nocturnal symptoms.[8]
Medications used in GERD
Medication Indication Recommendation
PPI therapy All patients without contraindications Use the lowest effective dose, safe during pregnancy
H2-receptor antagonist May be used as a complement to PPIs or as maintenance option in patients without erosive disease Beware tachyphylaxis after several weeks of usage
Prokinetic therapy and/or baclofen Used if symptoms do not improve Undergo diagnostic evaluation first
Sucralfate Pregnant women No role in non-pregnant patients


Do's

  • Differentiate heartburn from cardiac chest pain;
  • Consider a twice daily dosing in patients with night-time symptoms, variable schedules, and/or sleep disturbance;
  • Advise the patient to cease eating chocolate, caffeine, spicy foods, citrus or carbonated beverages;
  • Strongly recommend weight loss if patient's BMI is >25 or recent weight gain;
  • Recommend head of bed elevation if nocturnal GERD;
  • Advise against late evening meals;
  • Promote alcohol and tobacco cessation.
  • If there is an alarm symptom such as dysphagia
  • If there's no response with such measures and initial 8-week PPI treatment, refer patient to a specialist.

Don'ts

  • Do not request an upper endoscopy for every patient complaining of GERD;
  • Do not request manometry or ambulatory reflux monitoring routinely.

References

  1. American College of Obstetricians and Gynecologists’ Committee on Practice Bulletins—Obstetrics (2016). "Practice Bulletin No. 171: Management of Preterm Labor". Obstet Gynecol. 128 (4): e155–64. doi:10.1097/AOG.0000000000001711. PMID 27661654.
  2. Tibballs J, Watson T (2011). "Symptoms and signs differentiating croup and epiglottitis". J Paediatr Child Health. 47 (3): 77–82. doi:10.1111/j.1440-1754.2010.01892.x. PMID 21091577.
  3. Stroud RH, Friedman NR (2001). "An update on inflammatory disorders of the pediatric airway: epiglottitis, croup, and tracheitis". Am J Otolaryngol. 22 (4): 268–75. doi:10.1053/ajot.2001.24825. PMID 11464324.
  4. Yerian L, Fiocca R, Mastracci L, Riddell R, Vieth M, Sharma P; et al. (2011). "Refinement and reproducibility of histologic criteria for the assessment of microscopic lesions in patients with gastroesophageal reflux disease: the Esohisto Project". Dig Dis Sci. 56 (9): 2656–65. doi:10.1007/s10620-011-1624-z. PMID 21365241.
  5. "Gastro-oesophageal reflux disease and dyspepsia in adults: investigation and management". National Institute for Health and Care Excellence: Clinical Guidelines. 2019. PMID 31935049.
  6. "Heartburn vs. heart attack - Harvard Health".
  7. Bösner S, Haasenritter J, Becker A, Hani MA, Keller H, Sönnichsen AC; et al. (2009). "Heartburn or angina? Differentiating gastrointestinal disease in primary care patients presenting with chest pain: a cross sectional diagnostic study". Int Arch Med. 2: 40. doi:10.1186/1755-7682-2-40. PMC 2799444. PMID 20003376.
  8. 8.0 8.1 8.2 8.3 8.4 8.5 8.6 Katz PO, Gerson LB, Vela MF (2013). "Guidelines for the diagnosis and management of gastroesophageal reflux disease". Am J Gastroenterol. 108 (3): 308–28, quiz 329. doi:10.1038/ajg.2012.444. PMID 23419381.
  9. 9.0 9.1 "www.worldgastroenterology.org" (PDF).
  10. Moayyedi P, Lacy BE, Andrews CN, Enns RA, Howden CW, Vakil N (2017). "ACG and CAG Clinical Guideline: Management of Dyspepsia". Am J Gastroenterol. 112 (7): 988–1013. doi:10.1038/ajg.2017.154. PMID 28631728.


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CLAUDICATION

Overview

Claudication is the description of cramping muscle pain that occurs after a certain degree of exercise and is relieved by rest. Claudication is classically caused by peripheral arterial disease, in which an obstruction in artery of the lower limbs can lead to an insufficient blood flow which is not enough to supply the demands from the muscles of that region, but there are other conditions that can mimic its symptoms such as nerve root compression, spinal stenosis, hip arthritis, symptomatic Baker's cyst, venous claudication and chronic compartment syndrome.

Causes

Life Threatening Causes

There are no life-threatening causes, which include conditions which may result in death or permanent disability within 24 hours if left untreated.

Common Causes

Diagnosis

Shown below is a flowchart for diagnostic testing for suspected peripheral arterial disease according to the 2016 AHA/ACC guidelines:

 
 
 
 
 
 
 
 
 
Suspected PAD
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Symptoms:
Leg pain at rest
❑ Reduced or absent pulses
Leg pain during exertion
Gangrene
❑ Pale extremity
❑ Non healing wound
Calf or foot cramping
Paresthesias
 
 
Suspected critical limb ischemia
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Order Ankle brachial index
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
≤ 0.90
 
 
 
 
Normal
1.00-1.40
Borderline
0.91-0.99
 
 
 
 
 
 
 
> 1.40
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Order Exercise ankle-brachial index if exertion non-joint related leg symptoms
If absent - search for alternative diagnosis
 
 
 
 
 
 
 
Order Toe-Brachial Index
 
Exercise ankle-brachial index
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Does the patient have > 20% decrease in Postexercise ABI?
 
 
 
 
 
 
 
Is TBI < 0.7?
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Yes
 
 
No
 
 
No
 
 
Yes
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PAD confirmed
 
 
 
 
 
No PAD - search for alternative diagnosis
 
 
 
 
PAD confirmed
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Lifestyle-limited claudication despite guideline-directed management and therapy, revascularization considered
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Yes
 
 
 
 
 
 
No?
Continue guideline-directed management and therapy
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Anatomic assessment: (Class I)
❑ Duplex ultrasound
❑ Computed tomography angiography
❑ Magnetic resonance angiography
 
 
 
Anatomic assessment: (Class IIa)
❑ Invasive angiography
 
 
 
 
 
 
 
 
 
 
 
 


Shown below is a table summarizing the differential diagnosis of claudication according the age and clinical presentation:

Differential Diagnosis of Intermittent Claudication and Lower Limb Pain
In younger patients:
Diagnosis Clinical Features Diagnostic Method of Choice Treatment
Buerger's Disease Rare vasculitis mostly seen in young Asians males who are smokers. Causes inflammation and thrombosis of the arteries of the legs, feet, forearms, and hands. Conventional angiography - multilevel occlusions and segmental narrowing of the lower extremity arteries with extensive collateral flow showing a corkscrew or “tree root” appearance Smoking cessation
Extrinsic Compression by Bone Lesions Not a common cause, 40% of osteochondromas arise from the posterior aspect of distal femur compressing the femoral artery. MRI, limb x-ray or CT scan Excision of the lesion and repair of the affected artery
Popliteal Artery Entrapment Syndrome Common in young patients with claudication, especially athletes - compression of the popliteal artery by the medial head of the gastrocnemius muscle. Stress angiography Surgery
Fibromuscular Dysplasia Affects young women of childbearing age, affects mostly renal, cerebral and visceral arteries but may affect limbs as well. Angiography - string-of-beads appearance Angioplasty
Takayasu's Arteritis Rare vasculitis mostly seen on Asian and South American women. Stenosis of the abdominal aorta and iliac arteries are present in 17% of the patients and may cause claudication. Conventional angiography Corticosteroids, methotrexate, azathioprine, and cyclophosphamide
Cystic Adventitial Disease 1 in 1200 cases of claudication, most common in men, 20-50 years without risk factors for atherosclerosis. It is caused by repetitive trauma, which causes the formation of a mucin-containing cystic structure in the wall of the popliteal artery. Conventional angiography, MRI Complete excision of the cyst with prosthetic and vein replacement, as well as bypass
In older patients:
Spinal Stenosis Motor weakness is the most important symptom, which may be accompanied by pain. It starts soon after standing up, and may be relieved by sitting or bending (lumbar spine flexion) MRI Analgesic drugs, physical therapy, acupuncture or surgery (gold standard)
Peripheral Arterial Disease May present with absent or reduced peripheral pulses, and audible bruits but some patients may not present with these symptoms. A low ankle-brachial pressure index (<0.9) is suggestive of the disease but if normal it does not exclude it. An exercise ankle-brachial pressure index can be done on patients that doesn't present with these signs.

Other clinical features include: decreased skin temperature, shiny, hairless skin over the lower extremities, pallor on elevation of the extremity, dystrophic toenails, and rubor when the limb is dependent.

Handheld Doppler, conventional angiography Smoking cessation, antiplatelet drugs, statins, diabetes and blood pressure control, exercise, percutaneous transluminal angioplasty.
Nerve Root Compression Caused by compression of the nerve root by other structure, such as an herniated disc. The pain usually radiates down the back of the leg and is described as sharp lancinating pain. It may be relieved by adjusting the position of the back (leaning forward). MRI Surgery
Hip Arthritis Pain starts when the patient undergoes weight bearing and is worsened by activity. The pain is continuous and intensified by weight bearing, with inflammatory signs such as tenderness, swelling, and hyperthermia. MRI Surgery
Baker's Cyst Pain is worsened with activity, not relieved by resting, and may have tenderness and swelling behind the knee. Ultrasound, MRI Surgery

Treatment

Shown below is an algorithm summarizing the diagnosis of claudication due to peripheral arterial disease according the the British Medical Journal guidelines.

 
 
 
 
 
Evaluate affected limb - check for color and trophic changes, early ulcerations, skin temperature, capillary refill time, pulses at the groin and popliteal fossa, and the pedal pulses.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
If peripheral arterial disease is suspected: Screening test: ankle-brachial index (systolic blood pressure of the dorsalis pedis, posterior tibialis, or fibularis artery is obtained with a handheld Doppler and divided by the higher of the two brachial pressures) - if <0.9 confirms peripheral arterial disease.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Secondary prevention for coronary arterial disease: start aspirin 75mg daily and statins
 
Control cardiovascular risk factors (hyperglycemia, obesity, dyslipidemia, smoking)
 
Advise the patient to exercise for 30 minutes twice daily to increase pain-free walking and total walking distance by stimulating collateral blood flow)
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cilostazol may be used for improving symptoms[1]
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Be aware of the 5 Ps—pain, pale, pulseless, paraesthesia, paralysis—indicating an acute limb ischemia
 
 
 

Do's

  • Assess for peripheral arterial disease, as it is the most common cause for intermittent claudication, but do consider other causes depending on the age;
  • Confirm the diagnosis by measuring the ankle-brachial pressure indices;
  • Assess the risk factors for atherosclerosis and control them. Encourage patients to cease smoking, to control the blood glucose, prescribe antiplatelet drugs, optimize antihypertensive medication doses, start statins and encourage exercise;
  • If there's no improvement, symptoms are disabling or diagnosis is uncertain, refer to a specialist.[2]
  • Best treatment options for peripheral arterial disease are: open surgery, endovascular therapy, and exercise therapy. These were superior to medical management in achieve higher walking distance and managing claudication.
  • Antiplatelet drugs with either aspirin or clopidogrel alone is recommended to reduce myocardial infarction, stroke, and vascular death in patients with symptomatic PAD.[3]
  • In patients with claudication, supervised exercise programs increases functional status and reduce leg symptoms.[3]
  • Patients with diabetes mellitus should be oriented to perform self-foot examination and healthy foot behaviors. Quick diagnosis and treatment of foot infections can prevent amputation.[3]

Don'ts

  • Symptomatic treatment of the claudication and leg pain must not overshadow the reduction of cardiovascular risk, as these patients have a significantly increased risk of death.
  • When treating peripheral arterial disease, always attempt reducing symptoms with less invasive treatment options such as exercising, do not immediately refer patients to more invasive treatment options;
  • Don't forget to address other causes of claudication if the patient is presenting it at a younger age, or if the treatment doesn't improve the symptoms.
  • Do not perform invasive or non-invasive anatomic assessments for asymptomatic patients.[3]
  • In patients not at increased risk of peripheral arterial disease, and without history of physical examination findings suggestive of PAD, the ankle-brachial index is not recommended.[3]
  • Anticoagulation should not be used to reduce the risk of cardiovascular ischemic events in patients with PAD.[3]
  • Pentoxifylline is not effective for treatment of claudication.[3]

References

  1. Carman TL, Fernandez BB (2000). "A primary care approach to the patient with claudication". Am Fam Physician. 61 (4): 1027–32, 1034. PMID 10706155.
  2. 3.0 3.1 3.2 3.3 3.4 3.5 3.6


Template:WikiDoc Sources


COVID

Overview

COVID-19-associated multisystem inflammatory syndrome (also known as PIMS-TS - pediatric inflammatory multisystem syndrome temporally with SARS-CoV2 infection or MIS-C - multisystem inflammatory syndrome in children) is an uncommon clinical entity caused by SARS-CoV2 and seen mostly on children. It presents with: fever > 3 days and elevated markers of inflammation and 2 of the following 5 criteria: rash or conjunctivitis; hypotension or shock; myocardial dysfunction, pericarditis, valvulitis or coronary abnormalities; evidence of coagulopathy and/or acute gastrointestinal problems along with evidence of COVID-19. It seems to be a severe form of COVID-19 in children presenting with symptoms that can be challenging to differentiate from other pediatric infectious diseases such as toxic shock syndrome and Kawasaki disease. The pathophysiology of this form of SARS-CoV2 infection remains unknown.

Historical Perspective

  • Reports of a new febrile pediatric entity began to appear in late April 2020 during the COVID-19 pandemic in the Western Europe, characterized by systemic hyperinflammation, abdominal pain with gastrointestinal symptoms and multiorgan involvement affecting especially the myocardium causing cardiogenic shock which reminded the physicians of Kawasaki disease;
  • Cases of children with such symptoms were quickly identified in the New York City area, which was then the most heavily affected city in the U.S. by the COVID-19 pandemic;[1]
  • A report of 8 cases from Evelina London Children's Hospital was published on 6 May 2020, showing very prominent markers of inflammation such as ferritin, D-dimers, triglycerides, elevated cardiac enzymes, high NT-pro-BNP levels and troponin, being empirically treated with IVIG;[1]
  • In 22 May, an article from the Journal of Pediatric Infectious Diseases Society addressed some of the similarities and differences of this new entity with Kawasaki's disease, noting that the demographics affected was significantly different, as it was not seen in Asia despite the pandemic also affecting such countries, but it was affecting mostly children of African ethnicity. The author also differentiated some of the laboratory findings, resembling the macrophage activation syndrome and not Kawasaki's disease.[1]

Classification of Disease Severity of COVID-19-associated multisystem inflammatory syndrome

  • There is no established system for the classification of COVID-19-associated multisystem inflammatory syndrome.

Pathophysiology

  • The exact pathophysiological mechanism of COVID-19-associated multisystem inflammatory syndrome is unclear.
  • Since there is a lag time between COVID-19-associated multisystem inflammatory syndrome appearance and COVID-19 infection (median time: 25 days) it is suspected to be a post-infectious phenomenon related to IgG antibody-mediated enhancement of disease. There are two arguments that support this theory: the presence of IgG antibodies against SARS-CoV2 and the presence of the lag time between COVID-19 symptoms and COVID-19-associated multisystem inflammatory syndrome.
  • There is, however, another theory that states that it is still an acute viral presentation of the disease due to the fact that children presenting with such symptoms undergone exploratory laparotomy which found mesenteric adenitis, supporting GI infection. SARS-CoV2 is also known to easily infect enterocytes. Another interesting point to consider is that the worsening of illness has not been seen in patients with COVID-19 who are treated with convalescent plasma, which could have occurred if it was an antibody-mediated enhancement.[2]
  • There is another hypothesis for the cytokine storm seen on children with COVID-19-associated multisystem inflammatory syndrome is originated from the known ability of coronaviruses to block type I and type III interferon responses, delaying the cytokine storm in patients that could not control the viral replication on earlier phases of the disease.[2]

Differentiating Any Disease from other disease

Summary of laboratory parameters of a COVID-19-associated multisystem inflammatory syndrome cohort compared with the historic cohorts of Kawasaki Disease, Kawasaki Disease Shock Syndrome and Toxic Shock Syndrome[3]
Parameters COVID-19-associated multisystem inflammatory syndrome (PIMS-TS) Kawasaki Disease (KD) Kawasaki Disease Shock (KDS) Toxic Shock Syndrome (TSS)
Age (median, IQR) 9 (5.7-14) 2.7 (1.4-4.7) 3.8 (0.2-18) 7.38 (2.4-15.4)
Total white cell count (*10^9/L) 17 (12-22) 13.4 (10.5-17.3) 12.1 (7.9-15.5) 15.6 (7.5-20)
Neutrophil count (*10^9/L) 13 (10-19) 7.2 (5.1-9.9) 5.5 (3.2-10.3) 16.4 (12-22)
Lymphocyte count (*10^9/L) 0.8 (0.5-1.5) 2.8 (1.5-4.4) 1.6 (1-2.5) 0.63 (0.41, 1.13)
Hemoglobin (g/L) 92 (83-103) 111.0 (105-119) 107 (98-115) 114 (98-130)
Platelet number (10^9/L) 151 (104-210) 365.0 (288-462) 235 (138-352) 155 (92- 255)
C-reactive protein (mg/L) 229 (156-338) 67.0(40-150) 193 (83-237) 201 (122, 317)
ALT (IU/L) 42 (26-95) 42.0 (24-112) 73 (34-107) 30.00 (22.10, 49.25)
Albumin (g/L) 24 (21-27) 38.0 (35-41) 30 (27-35) 27.00 (21.00, 31.00)
Ferritin (ug/L) 610 (359-1280) 200 (143-243) 301 (228-337) -
NT-Pro-BNP (pg/ml) 788 (174-10548) 41 (12-102) 396 (57-1520) -
Troponin (ng/L) 45 (8-294) 10.0 (10-20) 10 (10-30) -
D-dimer (ng/ml) 3578 (2085- 8235) 1650 (970-2660) 2580 (1460- 2990) -

Epidemiology and Demographics

  • Poor prognostic factors include age over 5 years and ferritin larger than 1400 µg/L.

Age

  • Children aged age over 5 years seem to have a worse prognosis than younger ones.[5]
  • The median age found out in a study published by JAMA was 9 years.[3]

Gender

  • Most of the cases, estimated in two thirds, seem to happen in boys.[6][3]

Race

  • It seems to affect predominantly blacks and asians.[3][6]

Comorbidities

  • Clinical evidence of association with underlying diseases is still scarce since it is a rare presentation of COVID-19 in children and teenagers.

References

  1. 1.0 1.1 1.2
  2. 2.0 2.1
  3. 3.0 3.1 3.2 3.3 3.4
  4. 6.0 6.1



Overview

Multisystem Inflammatory Syndrome in Children (MIS-C) is a condition that causes inflammation of some parts of the body like heart, blood vessels, kidneys, digestive system, brain, skin, or eyes. According to recent evidence, it is suggested that children with MIS-C had antibodies against COVID-19 suggesting children had COVID-19 infection in the past. This syndrome appears to be similar in presentation to Kawasaki disease, hence also called Kawasaki -like a disease. It also shares features with staphylococcal and streptococcal toxic shock syndromes, bacterial sepsis, and macrophage activation syndromes.

Classification of Disease Severity of MIS-C

  • Mild Disease
  • Children with MIS-C fall under this category who-
    • require minimal to no respiratory support.
    • minimal to no organ injury
    • normotensive
    • Do not meet the criteria for ICU admission.
  • Severe Disease
  • Children with MIS-C fall under this category who-[1]
    • have significant oxygen requirements (HFNC, BiPAP, mechanical ventilation).
    • have a mild-severe organ injury and ventricular dysfunction.
    • have a vasoactive requirement.
    • meet the criteria for ICU admissions

Pathophysiology

  • The excat pathophysiological mechanism of MIS-C is unclear. Since there is a lag time between MIS-C appearance and COVID-19 infection it is suspected to be causing by antibody dependent enhancement.
  • Another hypothesis is that since coronavirus block type1 and type III interferons, it results in delayed cytokine response in children with initially high viral load or whose immune response is unable to control infections causing MIS-C. Therefore, IFN responses result in viral clearance when the viral load is low resulting in mild infection. However, when the viral load is high and /or immune system is not able to clear the virus, the cytokine storm result in multisystem inflammatory syndrome in children (MIS-C).[2]
  • It is also suspected that since MIS-C presents predominantly with gastrointestinal manifestations, it replicates predominantly in the gastrointestinal tract.[2]

Differentiating Any Disease from other disease

It should be differentiated from following diseases

  • Bacterial sepsis
  • Staphylococcal and streptococcal toxic shock syndrome
  • Kawasaki disease.
  • More information about the differential diagnosis could be found here.

Epidemiology and Demographics

  • According to a recent study among the 186 children with MIS-C, the rate of hospitalization was 12% between March 16 and April 15 and 88% between April 16 and May 20.
  • 80% of the children were admitted to the intensive care unit and 20% of the children required mechanical ventilation.
  • 4% of the children required extracorporeal membrane oxygenation.[3]
  • The mortality rate among 186 children with MIS-C was 2%.[3]

Age

  • Among the 186 children with MIS-C distribution of age group was[3]
    • <1yr-7%
    • 1-4yr-28%
    • 5-9yr-25%
    • 10-14yr-24%
    • 15-20yr-16%.

Gender

  • Among the 186 children with MIS-C

Comorbidities

  • Children with MIS-C had following underlying comorbidities.[3]
    • Clinically diagnosed Obesity-8%
    • BMI-Based Obesity-29%
    • Cardiovascular diasease-3%
    • Respiratory disease-18%
    • Autoimmune disease or immunocompromising condition-5%

Organ System Involved

  • 71% of children had involvement of at least four organ systems.[3]

The most common organ system involved in MIS-C children among a total of 186 children were.[3]

  • Gastrointestinal(92%)
  • Cardiovascular(80%)
  • Hematologic(76%)
  • Mucocutaneous(74%)
  • Pulmonary(70%)



COVID

Overview

COVID-19-associated multisystem inflammatory syndrome (also known as PIMS-TS - pediatric inflammatory multisystem syndrome temporally with SARS-CoV2 infection or MIS-C - multisystem inflammatory syndrome in children) is an uncommon clinical entity caused by SARS-CoV2 and seen mostly on children. It presents with: fever > 3 days and elevated markers of inflammation and 2 of the following 5 criteria: rash or conjunctivitis; hypotension or shock; myocardial dysfunction, pericarditis, valvulitis or coronary abnormalities; evidence of coagulopathy and/or acute gastrointestinal problems along with evidence of COVID-19. It seems to be a severe form of COVID-19 in children presenting with symptoms that can be challenging to differentiate from other pediatric infectious diseases such as toxic shock syndrome and Kawasaki disease. The pathophysiology of this form of SARS-CoV2 infection remains unknown.

Historical Perspective

  • Reports of a new febrile pediatric entity began to appear in late April 2020 during the COVID-19 pandemic in the Western Europe, characterized by systemic hyperinflammation, abdominal pain with gastrointestinal symptoms and multiorgan involvement affecting especially the myocardium causing cardiogenic shock which reminded the physicians of Kawasaki disease;
  • Cases of children with such symptoms were quickly identified in the New York City area, which was then the most heavily affected city in the U.S. by the COVID-19 pandemic;[4]
  • A report of 8 cases from Evelina London Children's Hospital was published on 6 May 2020, showing very prominent markers of inflammation such as ferritin, D-dimers, triglycerides, elevated cardiac enzymes, high NT-pro-BNP levels and troponin, being empirically treated with IVIG;[4]
  • In 22 May, an article from the Journal of Pediatric Infectious Diseases Society addressed some of the similarities and differences of this new entity with Kawasaki's disease, noting that the demographics affected was significantly different, as it was not seen in Asia despite the pandemic also affecting such countries, but it was affecting mostly children of African ethnicity. The author also differentiated some of the laboratory findings, resembling the macrophage activation syndrome and not Kawasaki's disease.[4]

Classification of Disease Severity of COVID-19-associated multisystem inflammatory syndrome

  • There is no established system for the classification of COVID-19-associated multisystem inflammatory syndrome.

Pathophysiology

  • The exact pathophysiological mechanism of COVID-19-associated multisystem inflammatory syndrome is unclear.
  • Since there is a lag time between COVID-19-associated multisystem inflammatory syndrome appearance and COVID-19 infection (median time: 25 days) it is suspected to be a post-infectious phenomenon related to IgG antibody-mediated enhancement of disease. There are two arguments that support this theory: the presence of IgG antibodies against SARS-CoV2 and the presence of the lag time between COVID-19 symptoms and COVID-19-associated multisystem inflammatory syndrome.
  • There is, however, another theory that states that it is still an acute viral presentation of the disease due to the fact that children presenting with such symptoms undergone exploratory laparotomy which found mesenteric adenitis, supporting GI infection. SARS-CoV2 is also known to easily infect enterocytes. Another interesting point to consider is that the worsening of illness has not been seen in patients with COVID-19 who are treated with convalescent plasma, which could have occurred if it was an antibody-mediated enhancement.[5]
  • There is another hypothesis for the cytokine storm seen on children with COVID-19-associated multisystem inflammatory syndrome is originated from the known ability of coronaviruses to block type I and type III interferon responses, delaying the cytokine storm in patients that could not control the viral replication on earlier phases of the disease.[5]

Differentiating Any Disease from other disease

Summary of laboratory parameters of a COVID-19-associated multisystem inflammatory syndrome cohort compared with the historic cohorts of Kawasaki Disease, Kawasaki Disease Shock Syndrome and Toxic Shock Syndrome[6]
Parameters COVID-19-associated multisystem inflammatory syndrome (PIMS-TS) Kawasaki Disease (KD) Kawasaki Disease Shock (KDS) Toxic Shock Syndrome (TSS)
Age (median, IQR) 9 (5.7-14) 2.7 (1.4-4.7) 3.8 (0.2-18) 7.38 (2.4-15.4)
Total white cell count (*10^9/L) 17 (12-22) 13.4 (10.5-17.3) 12.1 (7.9-15.5) 15.6 (7.5-20)
Neutrophil count (*10^9/L) 13 (10-19) 7.2 (5.1-9.9) 5.5 (3.2-10.3) 16.4 (12-22)
Lymphocyte count (*10^9/L) 0.8 (0.5-1.5) 2.8 (1.5-4.4) 1.6 (1-2.5) 0.63 (0.41, 1.13)
Hemoglobin (g/L) 92 (83-103) 111.0 (105-119) 107 (98-115) 114 (98-130)
Platelet number (10^9/L) 151 (104-210) 365.0 (288-462) 235 (138-352) 155 (92- 255)
C-reactive protein (mg/L) 229 (156-338) 67.0(40-150) 193 (83-237) 201 (122, 317)
ALT (IU/L) 42 (26-95) 42.0 (24-112) 73 (34-107) 30.00 (22.10, 49.25)
Albumin (g/L) 24 (21-27) 38.0 (35-41) 30 (27-35) 27.00 (21.00, 31.00)
Ferritin (ug/L) 610 (359-1280) 200 (143-243) 301 (228-337) -
NT-Pro-BNP (pg/ml) 788 (174-10548) 41 (12-102) 396 (57-1520) -
Troponin (ng/L) 45 (8-294) 10.0 (10-20) 10 (10-30) -
D-dimer (ng/ml) 3578 (2085- 8235) 1650 (970-2660) 2580 (1460- 2990) -

Epidemiology and Demographics

  • Poor prognostic factors include age over 5 years and ferritin larger than 1400 µg/L.

Age

  • Children aged age over 5 years seem to have a worse prognosis than younger ones.[8]
  • The median age found out in a study published by JAMA was 9 years.[6]

Gender

  • Most of the cases, estimated in two thirds, seem to happen in boys.[9][6]

Race

  • It seems to affect predominantly blacks and asians.[6][9]

Comorbidities

  • Clinical evidence of association with underlying diseases is still scarce since it is a rare presentation of COVID-19 in children and teenagers.

References

  1. 2.0 2.1
  2. 3.0 3.1 3.2 3.3 3.4 3.5
  3. 4.0 4.1 4.2
  4. 5.0 5.1
  5. 6.0 6.1 6.2 6.3 6.4
  6. 9.0 9.1



Overview

Multisystem Inflammatory Syndrome in Children (MIS-C) is a condition that causes inflammation of some parts of the body like heart, blood vessels, kidneys, digestive system, brain, skin, or eyes. According to recent evidence, it is suggested that children with MIS-C had antibodies against COVID-19 suggesting children had COVID-19 infection in the past. This syndrome appears to be similar in presentation to Kawasaki disease, hence also called Kawasaki -like a disease. It also shares features with staphylococcal and streptococcal toxic shock syndromes, bacterial sepsis, and macrophage activation syndromes.

Classification of Disease Severity of MIS-C

  • Mild Disease
  • Children with MIS-C fall under this category who-
    • require minimal to no respiratory support.
    • minimal to no organ injury
    • normotensive
    • Do not meet the criteria for ICU admission.
  • Severe Disease
  • Children with MIS-C fall under this category who-[1]
    • have significant oxygen requirements (HFNC, BiPAP, mechanical ventilation).
    • have a mild-severe organ injury and ventricular dysfunction.
    • have a vasoactive requirement.
    • meet the criteria for ICU admissions

Pathophysiology

  • The excat pathophysiological mechanism of MIS-C is unclear. Since there is a lag time between MIS-C appearance and COVID-19 infection it is suspected to be causing by antibody dependent enhancement.
  • Another hypothesis is that since coronavirus block type1 and type III interferons, it results in delayed cytokine response in children with initially high viral load or whose immune response is unable to control infections causing MIS-C. Therefore, IFN responses result in viral clearance when the viral load is low resulting in mild infection. However, when the viral load is high and /or immune system is not able to clear the virus, the cytokine storm result in multisystem inflammatory syndrome in children (MIS-C).[2]
  • It is also suspected that since MIS-C presents predominantly with gastrointestinal manifestations, it replicates predominantly in the gastrointestinal tract.[2]

Differentiating Any Disease from other disease

It should be differentiated from following diseases

  • Bacterial sepsis
  • Staphylococcal and streptococcal toxic shock syndrome
  • Kawasaki disease.
  • More information about the differential diagnosis could be found here.

Epidemiology and Demographics

  • According to a recent study among the 186 children with MIS-C, the rate of hospitalization was 12% between March 16 and April 15 and 88% between April 16 and May 20.
  • 80% of the children were admitted to the intensive care unit and 20% of the children required mechanical ventilation.
  • 4% of the children required extracorporeal membrane oxygenation.[3]
  • The mortality rate among 186 children with MIS-C was 2%.[3]

Age

  • Among the 186 children with MIS-C distribution of age group was[3]
    • <1yr-7%
    • 1-4yr-28%
    • 5-9yr-25%
    • 10-14yr-24%
    • 15-20yr-16%.

Gender

  • Among the 186 children with MIS-C

Comorbidities

  • Children with MIS-C had following underlying comorbidities.[3]
    • Clinically diagnosed Obesity-8%
    • BMI-Based Obesity-29%
    • Cardiovascular diasease-3%
    • Respiratory disease-18%
    • Autoimmune disease or immunocompromising condition-5%

Organ System Involved

  • 71% of children had involvement of at least four organ systems.[3]

The most common organ system involved in MIS-C children among a total of 186 children were.[3]

  • Gastrointestinal(92%)
  • Cardiovascular(80%)
  • Hematologic(76%)
  • Mucocutaneous(74%)
  • Pulmonary(70%)
  • Historical perspective




External links

Classification
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External resources

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Tuberous sclerosis skin lesion - Angiofibromas - image taken from: www.atlasdermatologico.com.br
Tuberous sclerosis skin lesion - Ash-leaf spot - image taken from: www.atlasdermatologico.com.br
Tuberous sclerosis skin lesion - Ungual fibroma - image taken from: www.atlasdermatologico.com.br

Overview

Tuberous sclerosis complex (TSC), is a rare autosomal dominant congenital disorder that affects multiple organ systems and is characterized by an abnormal growth of ectodermal and mesodermal cells that causes non-cancerous tumours to grow in the brain and on other vital organs such as the kidneys, heart, liver, eyes, lungs, and skin. [4]

A combination of symptoms may include seizures, intellectual disability, developmental delay, behavioral problems, skin abnormalities, and lung and kidney disease. TSC is caused by a mutation of either of two genes, TSC1 and TSC2, which code for the proteins hamartin and tuberin, respectively. These proteins act as tumor growth suppressors, agents that regulate cell proliferation and differentiation.[5]

The disease presents with a myriad of symptoms, having been described by multiple doctors throughtout the 19th century and called by many different names, but it is now called tuberous sclerosis complex, and the relationship between benign brain tumors and the symptoms of the disease was first described by Désiré-Magloire Bourneville in 1880. [6]

Historical Perspective

Tuberous Sclerosis was described as a specific disease in the 19th century, being initially referred to adenoma sebaceum, epiloia, Pringle's disease or Bourneville's disease. Rayer, a French dermatologist, was the one to first describe the disease and the fibrovascular papules that characterize it, making illustrations of it. He described two cases of tuberous sclerosis in patients who had the nasolabial papular eruption with telangiectasias at the base. In 1850 the first written report of tuberous sclerosis appeared in "Vitiligoidea", published by Addison and Gull. It was not recognized as a distinct disease but was classified as "vitiligoidea tuberosa". In 1862, von Recklinghausen reported a tumor of the heart found in a newborn during autopsy, and by that he is credited to be the first that described the microscopic appearance of tuberous sclerosis. Bourneville in 1880, a French neurologist, described the case of a girl who presented at the age of 3 with facial eruption and died at 15 years of age due to epilepsy, which complicated with pneumonia and inanition. He found brain and kidney tumors on the autopsy which were correctly believed to be the cause of her seizures and mental retardation. In 1911, E. B. Sherlock, superintendent of Belmont Asylum of Idiots, London, coined the word "epiloia" that indicated a clinical triad of epilepsy, low intelligence and adenoma sebaceum.[6]

In 2002, treatment with rapamycin was found to be effective at shrinking tumours in animals. This has led to human trials of rapamycin as a drug to treat several of the tumors associated with TSC.[7]

Classification

There is no established system for the classification of tuberous sclerosis.

Pathophysiology

Patients with tuberous sclerosis have loss-of-function germline mutations in both alleles of the following tumor suppressor genes: TSC1 or TSC2. One third of the mutations is inherited, two thirds are de novo mutations. The mutations causes the loss of one allele, but as long as the second one remains intact, the cell won't present any metabolic change. When there is a second TSC1 or TSC2 mutation, which typically occurs in multiple cells over a person's lifetime, then the disease starts to manifest (fitting the "two-hit" tumor-suppressor gene model, with the germline mutation inactivating one gene and then a somatic event inactivating the remaining other one). TSC1 codes for a protein called hamartin, and TSC2 codes for a protein called tuberin. They belong to a protein complex that inhibits the mammalian target of rapamycin (mTOR) complex 1 via RAS homologue enriched in brain (RHEB) which regulates cell growth. In a normal patient, RHEB activates mTORC1 when bound to GTP, but in TSC there is a hyperactivarion of RHEB and consequently of mTORC1. mTOR regulates cellular proliferation, autophagy, growth and protein and lipid synthesis and it enhances protein translation when activated, reprograming the cell metabolism, which increases cell proliferation but also may make it vulnerable to death in nutrient-restricted media. Besides the TSC-RHEB-mTORC1 pathway, there is evidence of alternate pathways also having a role in the disease that are mTORC1 independent, but they are currently under investigation.[8][4]

Causes

Loss of function mutation of the genes TSC1 and TSC2 which are responsible for the production of hamartin and tuberin. These proteins regulate the cell cycle. Damage to this pathway leads to a very variable presentation of benign tumors in multiple systems. TSC1 and TSC2 are both tumor suppressor genes that function according to Knudson's "two hit" hypothesis. That is, a second random mutation must occur before a tumor can develop. This explains why, despite its high penetrance, TSC has wide expressivity.[4]

Differentiating Tuberous Sclerosis from other Diseases

Tuberous sclerosis must be differentiated from other diseases that cause myxoma or other benign tumors and/or seizures, such as Sturge Weber, hypomelanosis of Ito, Birt-Hogg-Dube syndrome, multiple endocrine neoplasia and various seizures disorders.[9]

Epidemiology and Demographics

Tuberous sclerosis complex affects about 1 in 6,000 people, occurring in all races and ethnic groups, and in both genders. Prior to the invention of CT scanning to identify the nodules and tubers in the brain, the prevalence was thought to be much lower and the disease associated with those people diagnosed clinically with learning disability, seizures, and facial angiofibroma. Whilst still regarded as a rare disease, TSC is common when compared to many other genetic diseases, with at least 1 million individuals worldwide.[10][11]

Risk Factors

There are no established environmental risk factors for tuberous sclerosis. One third of the cases are familial, so family history can be a risk factor for the disease.[4]

Screening

As it is a rare disease, screening is not recommended.

Natural History, Complications, and Prognosis

Skin

Symptoms develop in almost all patients with TSC and include ungual fibromas, facial angiofibromas (may demand treatment and may worsen with UV exposure), shagreen patches (oval-shaped lesions, generally skin-colored but can be sometimes pigmented, may be crinkled or smooth), focal hypopigmented macules (ash-leaf spots), dental enamel pits (present in 100% of the patients), oral fibromas, retinal astrocytic hamartomas (tumors of the retinal nerve), retinal achromic patches (light or dark spots on the eye).[4]

Renal

TSC leads to the formation of renal angiomyolipomas (present in 60-80% of the TSC patients), benign tumors composed of abnormal vessels, smooth-muscle cells and fat cells which may cause hematuria. These tumors can be detectable in early childhood by MRI, CT or ultrasound. Although benign, in TSC they are commonly multiple and bilateral. Angiomyolipomas larger than 4 cm are at risk for potentially catastrophic hemorrhage either spontaneously or with minimal trauma. Patients may also develop epithelial cysts, polycystic kidney disease (as 2-3% of the patients carries a deletion that affects both TSC2 gene and one of the genes that lead to autosomal dominant polycystic kidney disease) and renal-cell carcinomas that may be diagnosed at a younger age (mean 28 years).[12][4] Patients ≥18 years may have higher rates of chronic kidney disease, hematuria, kidney failure, embolization (EMB), and partial and complete nephrectomy compared to patients <18 years.[13]

Pulmonary

Lymphangiomyomatosis affects mostly women and is a proliferation of smooth-muscle cells that may result in cystic changes in the lungs. Recent genetic analysis has shown that the proliferative bronchiolar smooth muscle in TSC-related lymphangioleiomyomatosis is monoclonal metastasis from a coexisting renal angiomyolipoma. Cases of TSC-related lymphangioleiomyomatosis recurring following lung transplant have been reported.[14] Diagnosed mostly during early adulthood, may cause pneumothorax. Multifocal micronodular pneumocyte hyperplasia can occur in both men and women and are mostly asymptomatic.[12][4]

In 2020 a paper showed that epilepsy remission by appropriate treatment in early life can possibly prevent autism and intellectual disability.[15]

Neurologic

These manifestations are one of the major causes of morbidity in patients with TSC. TSC may cause epilepsy, which is the most common neurological presentation occurring in 70-80% of patients and may complicate with infantile spasms, a severe form of epileptic syndrome. If epilepsy presents with an early onset t is associated with cognitive disabilities, which are also very prevalent in such patients. Neuropsychiatric disorders are present in two-thirds of the patients and anxiety is one of the most common presentations. Autism is one possible manifestation and is especially associated with cerebral cortical tubers. It consists of neurologic tissue that grows in a different pattern, losing the normal six-layered cortical structure, with dysmorphic neurons, large astrocytes and giant cells. Some patients may also present with subependymal giant cell astrocytomas, which may cause obstructive hydrocephalus. Risk of such benign tumors decreases after age of 20.[12][4]

Cardiovascular

Rhabdomyomas may be present, being intramural or intracavitary in its distribution along the myocardium. May be detected in utero on fetuses and is associated with cardiac failure. Often disappear spontaneously in later life.[4] 80% of children under two-years-old with TSC have at least one rhabdomyoma, and about 90% of those will have several.[16]

Diagnosis

Tuberous sclerosis complex is diagnosed if a set of diagnostic criteria are met. These criteria include major and minor features. If a case meets the clinical diagnostic criteria, then it is performed a genetic molecular testing which is seem mostly as corroborative. Most of the patients seek medical assistance due to their dermatologic lesions or seizures but for making this diagnosis an evaluation that assesses all the clinical features of the tuberous sclerosis complex is necessary, as these manifestations have variable penetrance.[12] The latest diagnostic criteria was developed by the 2012 International Tuberous Sclerosis Complex Consensus Conference, and it is showed at the table below:

Diagnostic Criteria for Tuberous Sclerosis Complex[17]
Major Features
Location Sign Onset[12] Note
1 Skin Hypomelanotic macules Infant – child At least three, at least 5 mm in diameter.
2 Head Facial angiofibromas or fibrous cephalic plaque Infant – adult At least three angiofibromas
3 Fingers and toes Ungual fibroma Adolescent – adult At least two
4 Skin Shagreen patch (connective tissue nevus) Child
5 Eyes Multiple retinal nodular hamartomas Infant
6 Brain Cortical dysplasias (includes tubers and cerebral white matter radial migration lines) Fetus
7 Brain Subependymal nodule Child – adolescent
8 Brain Subependymal giant cell astrocytoma Child – adolescent
9 Heart Cardiac rhabdomyoma Fetus
10 Lungs Lymphangioleiomyomatosis Adolescent – adult
11 Kidneys Renal angiomyolipoma Child – adult At least two. Together, 10 and 11 count as one major feature.
Minor Features
Location Sign Note
1 Skin "Confetti" skin lesions
2 Teeth Dental enamel pits At least three
3 Gums Intraoral fibromas At least two
4 Eyes Retinal achromic patch
5 Kidneys Multiple renal cysts
6 Liver, spleen and other organs Nonrenal hamartoma

TSC can be first diagnosed at any stage of life. Prenatal diagnosis is possible by chance if heart tumours are discovered during routine ultrasound. In infancy, white patches on the skin may be noticed, or the child may present with epilepsy, particularly infantile spasms, or developmental delay may lead to neurological tests. In childhood, behavioural problems and autism spectrum disorder may also lead to a clinical investigation and a diagnosis. During adolescence it is usually that skin problems appear while in adulthood, kidney and lung problems may become evident. An individual may also be diagnosed at any time as a result of genetic testing of family members of another affected person.[18]

History and Symptoms

The most common symptoms of tuberous sclerosis are due to the growth of the already disclosed benign tumors. Tumors in the CSN may cause epilepsy, autism and children may also present with cognitive disabilities. Tumors in the kidneys may compromise renal function and metastasize to the lungs, which in most cases is asymptomatic. Tumors in the heart may compromise heart function, but they tend to spontaneously disappear later in life.

Physical Examination

Physical examination of patients with tuberous sclerosis is a very rich one due to the different skin lesions that the disease can cause and it is usually remarkable for dental enamel pits (present in 100% of the patients)[4],hypomelanotic macules, shagreen patches, and forehead plaques.[19]

Laboratory Findings

There are no typical diagnostic laboratory findings associated with tuberous sclerosis. Patients may present with elevated BUN or creatinine if their renal angiomyolipomas compromise renal function or if they also present with autosomal dominant polycystic kidney disease.

Electrocardiogram

There are no ECG findings associated with tuberous sclerosis.

X-ray

There are no typical x-ray findings associated with tuberous sclerosis, but patients may present with pneumothorax and/or chylous pleural effusions due if they develop lymphangioleiomyomatosis.

Echocardiography or Ultrasound

Echocardiography/ultrasound may be helpful raising the suspicion of tuberous sclerosis. Echocardiographs can detect cardiac rhabdomyomas, present in more than 80% of the children with TSC. Ultrasound can detect hepatic angiomyolipomas, renal angiomyolipomas (present in 55-75% of patients) and renal cysts (present in 18-55% of the patients).[20]

CT scan

CT scan may be helpful in the diagnosis of tuberous sclerosis. It can diagnose cortical or subependymal tubers and white matter abnormalities, subependymal hamartomas, subependymal giant cell astrocytomas, renal angiomyolipomas, renal cysts, renal cell carcinoma (associated with tuberous sclerosis), retroperitoneal lymphangiomyomatosis, gastrointestinal polyps, pancreatic neuroendocrine tumors, lymphangioleiomyomatosis, multifocal micronodular pneumocyte hyperplasia and cardiac rhabdomyomas.[20]

MRI

MRI may be helpful in the diagnosis of tuberous sclerosis as it can find the same abnormalities found on CT scan which are described above, some of them with much more detail, but it is especially useful for evaluating white matter changes seen in the disease.[20]

Other Imaging Findings

There are no other imaging findings associated with tuberous sclerosis.

Other Diagnostic Studies

Genetic testing may be helpful in the diagnosis of tuberous sclerosis but some patients may not have detectable genetic mutations on the test and still have the disease. It is considered to be a corroborative test.

Treatment

Tuberous sclerosis complex affects multiple organ systems so a multidisciplinary team of medical professionals is required.

Screening of complications:

In suspected or newly diagnosed TSC, the following tests and procedures are recommended by 2012 International Tuberous Sclerosis Complex Consensus Conference.[21]

  • Take a personal and family history covering three generations. Genetic counselling and tests determine if other individuals are at risk.
  • A magnetic resonance imaging (MRI) of the brain to identify tubers, subependymal nodules (SEN) and sub-ependymal giant cell astrocytomas (SEGA).
  • Children undergo a baseline electroencephalograph (EEG) and family educated to identify seizures if/when they occur.
  • Assess children for behavioural issues, autism spectrum disorder, psychiatric disorders, developmental delay, and neuropsychological problems.
  • Scan the abdomen for tumours in various organs, but most importantly angiomyolipomata in the kidneys. MRI is superior to CT or ultrasound. Take blood pressure and test renal function.
  • In adult women, test pulmonary function and perform a high-resolution computed tomography (HRCT) of the chest.
  • Examine the skin under a Wood's lamp (hypomelanotic macules), the fingers and toes (ungual fibroma), the face (angiofibromas), and the mouth (dental pits and gingival fibromas).
  • In infants under three, perform an echocardiogram to spot rhabdomyomas, and electrocardiogram (ECG) for any arrhythmia.
  • Use a fundoscope to spot retinal hamartomas or achromic patches.

Treatment:

The various symptoms and complications from TSC may appear throughout life, requiring continued surveillance and adjustment to treatments. The following ongoing tests and procedures are recommended by 2012 International Tuberous Sclerosis Complex Consensus Conference:[21]

  • In children and adults younger than 25 years, a magnetic resonance imaging (MRI) of the brain is performed every one to three years to monitor for subependymal giant cell astrocytoma (SEGA). If a SEGA is large, growing or interfering with ventricles, the MRI is performed more frequently. After 25 years, if there are no SEGAs then periodic scans may no longer be required. A SEGA causing acute symptoms are removed with surgery, otherwise either surgery or drug treatment with an mTOR inhibitor may be indicated.
  • Repeat screening for TSC-associated neuropsychiatric disorders (TAND) at least annually. Sudden behavioural changes may indicate a new physical problem (for example with the kidneys, epilepsy or a SEGA).
  • Routine EEG determined by clinical need.
  • Infantile spasms are best treated with vigabatrin and adrenocorticotropic hormone used as a second-line therapy. Other seizure types have no TSC-specific recommendation, though epilepsy in TSC is typically difficult to treat (medically refractory).
  • Repeat MRI of abdomen every one to three years throughout life. Check renal (kidney) function annually. Should angiomyolipoma bleed, this is best treated with embolisation and then corticosteroids. Removal of the kidney (nephrectomy) is strongly to be avoided. An asymptomatic angiomyolipoma that is growing larger than 3cm is best treated with an mTOR inhibitor drug. Other renal complications spotted by imaging include polycystic kidney disease and renal cell carcinoma.
  • Repeat chest HRCT in adult women every five to 10 years. Evidence of lymphangioleiomyomatosis (LAM) indicates more frequent testing. An mTOR inhibitor drug can help, though a lung transplant may be required.
  • A 12-lead ECG should be performed every three to five years.

The mTOR inhibitor everolimus was approved in the US for treatment of TSC-related tumors in the brain (subependymal giant cell astrocytoma) in 2010 and in the kidneys (renal angiomyolipoma) in 2012.[22][23]  Everolimus also showed evidence of effectiveness at treating epilepsy in some people with TSC.[24][25] In 2017, the European Commission approved everolimus for treatment of refractory partial-onset seizures associated with TSC.[26]

Neurosurgical intervention may reduce the severity and frequency of seizures in TSC patients.[27] [28] Embolization and other surgical interventions can be used to treat renal angiomyolipoma with acute hemorrhage. Surgical treatments for symptoms of lymphangioleiomyomatosis (LAM) in adult TSC patients include pleurodesis to prevent pneumothorax and lung transplantation in the case of irreversible lung failure.[21]

Other treatments that have been used to treat TSC manifestations and symptoms include a ketogenic diet for intractable epilepsy and pulmonary rehabilitation for LAM.[29] Facial angiofibromas can be reduced with laser treatment and the effectiveness of mTOR inhibitor topical treatment is being investigated. Laser therapy is painful, requires anaesthesia, and has risks of scarring and dyspigmentation.[30]

References

  1. 2.0 2.1
  2. 3.0 3.1 3.2 3.3 3.4 3.5
  3. 4.0 4.1 4.2 4.3 4.4 4.5 4.6 4.7 4.8 4.9 Henske, Elizabeth P., et al. "Tuberous sclerosis complex." Nature reviews Disease primers 2.1 (2016): 1-18.
  4. "Tuberous Sclerosis Fact Sheet". National Institute of Neurological Disorders and Stroke. 2018-07-06. Retrieved 16 December 2018.
  5. 6.0 6.1 Morgan, J. Elizabeth, and Francis Wolfort. "The early history of tuberous sclerosis." Archives of dermatology 115.11 (1979): 1317-1319.
  6. Rott HD, Mayer K, Walther B, Wienecke R (March 2005). "Zur Geschichte der Tuberösen Sklerose (The History of Tuberous Sclerosis)" (PDF) (in German). Tuberöse Sklerose Deutschland e.V. Archived from the original (PDF) on 15 March 2007. Retrieved 8 January 2007.
  7. NIH - Tuberous Sclerosis - https://ghr.nlm.nih.gov/condition/tuberous-sclerosis-complex#genes - accessed at 06/10/2020
  8. NORD: National Organization for Rare Diseases - Tuberous Sclerosis - available at: https://rarediseases.org/rare-diseases/tuberous-sclerosis/#:~:text=Examples%20of%20such%20disorders%20include,be%20differentiated%20from%20tuberous%20sclerosis. accessed at 06/12/2020
  9. Curatolo, Paolo, ed. Tuberous sclerosis complex: from basic science to clinical phenotypes. Cambridge University Press, 2003.
  10. NIH - Tuberous Sclerosis - https://ghr.nlm.nih.gov/condition/tuberous-sclerosis-complex#genes - accessed at 06/10/2020
  11. 12.0 12.1 12.2 12.3 12.4 Crino PB, Nathanson KL, Henske EP (September 2006). "The tuberous sclerosis complex". The New England Journal of Medicine. 355 (13): 1345–56. doi:10.1056/NEJMra055323. PMID 17005952.
  12. Song, Xue, et al. "Natural history of patients with tuberous sclerosis complex related renal angiomyolipoma." Current medical research and opinion 33.7 (2017): 1277-1282.
  13. Henske EP (December 2003). "Metastasis of benign tumor cells in tuberous sclerosis complex". Genes, Chromosomes & Cancer. 38 (4): 376–81. doi:10.1002/gcc.10252. PMID 14566858.
  14. Gupta, Ajay, et al. "Epilepsy and neurodevelopmental comorbidities in tuberous sclerosis complex: a natural history study." Pediatric Neurology (2020).
  15. Hinton RB, Prakash A, Romp RL, Krueger DA, Knilans TK (November 2014). "Cardiovascular manifestations of tuberous sclerosis complex and summary of the revised diagnostic criteria and surveillance and management recommendations from the International Tuberous Sclerosis Consensus Group". Journal of the American Heart Association. 3 (6): e001493. doi:10.1161/JAHA.114.001493. PMC 4338742. PMID 25424575.
  16. Northrup H, Krueger DA (October 2013). "Tuberous sclerosis complex diagnostic criteria update: recommendations of the 2012 International Tuberous Sclerosis Complex Consensus Conference". Pediatric Neurology. 49 (4): 243–54. doi:10.1016/j.pediatrneurol.2013.08.001. PMC 4080684. PMID 24053982.
  17. "Tuberous Sclerosis Complex". University Hospitals Birmingham NHS Foundation Trust. Retrieved 16 December 2018.
  18. Curatolo P, ed. (2003). "Diagnostic Criteria". Tuberous Sclerosis Complex: From Basic Science to Clinical Phenotypes. International review of child neurology. London: Mac Keith Press. ISBN 978-1-898683-39-1. OCLC 53124670.
  19. 20.0 20.1 20.2 Radiopaedia - tuberous sclerosis - available at: https://radiopaedia.org/articles/tuberous-sclerosis accessed at 06/15/2020
  20. 21.0 21.1 21.2 Krueger DA, Northrup H (October 2013). "Tuberous sclerosis complex surveillance and management: recommendations of the 2012 International Tuberous Sclerosis Complex Consensus Conference". Pediatric Neurology. 49 (4): 255–65. doi:10.1016/j.pediatrneurol.2013.08.002. PMC 4058297. PMID 24053983.
  21. "Press Announcements - FDA approves Afinitor for non-cancerous kidney tumors caused by rare genetic disease". www.fda.gov. Retrieved 2017-02-08.
  22. "FDA Approval for Everolimus". National Cancer Institute. Retrieved 2017-02-08.
  23. French JA, Lawson JA, Yapici Z, Ikeda H, Polster T, Nabbout R, Curatolo P, de Vries PJ, Dlugos DJ, Berkowitz N, Voi M, Peyrard S, Pelov D, Franz DN (October 2016). "Adjunctive everolimus therapy for treatment-resistant focal-onset seizures associated with tuberous sclerosis (EXIST-3): a phase 3, randomised, double-blind, placebo-controlled study". Lancet. 388 (10056): 2153–63. doi:10.1016/s0140-6736(16)31419-2. PMID 27613521.
  24. Capal JK, Franz DN (2016). "Profile of everolimus in the treatment of tuberous sclerosis complex: an evidence-based review of its place in therapy". Neuropsychiatric Disease and Treatment. 12: 2165–72. doi:10.2147/NDT.S91248. PMC 5003595. PMID 27601910.
  25. AG, Novartis International. "Novartis drug Votubia® receives EU approval to treat refractory partial-onset seizures in patients with TSC". GlobeNewswire News Room. Retrieved 2017-02-08.
  26. Asano E, Juhász C, Shah A, Muzik O, Chugani DC, Shah J, Sood S, Chugani HT (July 2005). "Origin and propagation of epileptic spasms delineated on electrocorticography". Epilepsia. 46 (7): 1086–97. doi:10.1111/j.1528-1167.2005.05205.x. PMC 1360692. PMID 16026561.
  27. Chugani HT, Luat AF, Kumar A, Govindan R, Pawlik K, Asano E (August 2013). "α-[11C]-Methyl-L-tryptophan--PET in 191 patients with tuberous sclerosis complex". Neurology. 81 (7): 674–80. doi:10.1212/WNL.0b013e3182a08f3f. PMC 3775695. PMID 23851963.
  28. Hong AM, Turner Z, Hamdy RF, Kossoff EH (August 2010). "Infantile spasms treated with the ketogenic diet: prospective single-center experience in 104 consecutive infants". Epilepsia. 51 (8): 1403–407. doi:10.1111/j.1528-1167.2010.02586.x. PMID 20477843.
  29. Jacks SK, Witman PM (September–October 2015). "Tuberous Sclerosis Complex: An Update for Dermatologists". Pediatric Dermatology. 32 (5): 563–70. doi:10.1111/pde.12567. PMID 25776100.

External links

Classification
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External resources

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Case courtesy of Dr Ian Bickle, Radiopaedia.org, rID: 76157




 
 
 
 
 
 
 
Syncope classification
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vasovagal
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Micturation
 
 
 
 
 
 
 
 
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Case courtesy of Dr Vinay V Belaval, Radiopaedia.org, rID: 66974


Disease Type Sign Symptom



Syncope is classified into three categories:



Disease Name Age of Onset Gender Preponderance Signs/Symptoms Imaging Feature(s) Macroscopic Feature(s) Microscopic Feature(s) Laboratory Findings(s) Other Feature(s) ECG view

end of Tuberous Sclerosis

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Aortic aneurysm 22.jpg
Atherosclerotic Aneurysm: Gross, an excellent example, natural color, external view of typical thoracic aortic aneurysms
Image courtesy of Professor Peter Anderson DVM PhD and published with permission © PEIR, University of Alabama at Birmingham, Department of Pathology

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For patient information on Thoracic aortic aneurysm, click here

For patient information on Abdominal aortic aneurysm, click here

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [7], Associate Editor(s)-in-Chief: Lina Ya'qoub, MD Associate Editor-In-Chief: Cafer Zorkun, M.D., Ph.D. [8]

Overview

An aortic aneurysm is a dilation of the aorta in which the aortic diameter is ≥ 3.0 cm if abdominal[1] or >4 cm if thoracic[2], usually representing an underlying weakness in the wall of the aorta at that location. While the stretched vessel may occasionally cause discomfort, a greater concern is the risk of rupture which causes severe pain, massive internal hemorrhage which are often fatal. Aneurysms often are a source of blood clots (emboli) stemming from the most common etiology of atherosclerosis.

Classification

There are 2 types of aortic aneurysms: thoracic and abdominal. These can be further classified according to the respective part of the vessel that's been affected:

  • Thoracic aortic aneurysm, which occur in the thoracic aorta (runs through the chest);
  • Abdominal aortic aneurysm, which occur in the abdominal aorta, are the most common.
    • Suprarenal - not as common, often more difficult to repair surgically due to the presence of many aortic branches;
    • Infrarenal - often more easily surgically repaired and more common;
    • Pararenal - aortic aneurysm is infrarenal but affects renal arteries;
    • Juxtarenal - infrarenal aortic aneurysm that affects the aorta just below the renal arteries.

Aortic aneurysms may also be classified according to Crawford classification into 5 subtypes/groups:

  • Type 1: from the origin of left subclavian artery in descending thoracic aorta to the supra-renal abdominal aorta.
  • Type 2: from the left subclavian to the aorto-iliac bifurcation.
  • Type 3: from distal thoracic aorta to the aorto-iliac bifurcation
  • Type 4: limited to abdominal aorta below the diaphragm
  • Type 5: from distal thoracic aorta to celiac and superior mesenteric origins, but not the renal arteries.[3]

Historical Perspective

Aortic aneurysm was first recorded by Antyllus, a Greek surgeon, in the second century AD. In the Renaissaince era, in 1555, Vesalius first diagnosed an abdominal aortic aneurysm. The first publication on the pathology with case studies was published by Lancisi in 1728. Finally, in 1817, Astley Cooper was the first surgeon to ligate the abdominal aorta to treat a ruptured iliac aneurysm. In 1888, Rudoff Matas came up with the concept of endoaneurysmorrhaphy.[4]

Pathophysiology

The aortic aneurysms are a multifactorial disease associated with genetic and environmental risk factors. Marfan's syndrome and Ehlers-Danlos syndrome are associated with the disease, but there are also rarer syndromes like the Loeys-Dietz syndrome that are associated as well. Even in patients that do not have genetic syndromes, it has been observed that genetics can also play a role on aortic aneurysms' development. There has been evidence of genetic heterogeneity as there has already been documented in intracranial aneurysms.[5] The genetic alterations associated with these genetic syndromes are the following:

Genetic diseases associated with aortic aneurysms [6]
Disease Involved Cellular Pathway Mutated Gene(s) Affected Protein(s)
Ehlers-Danlos type IV syndrome Extracellular Matrix Proteins COL3A1 Collagen type III
Marfan's Syndrome Extracellular Matrix Proteins FBN1 Fibrillin-1
Loeys-Dietz syndrome TGF-β Pathway TGFBR1/TGFBR2
Aneurysm-Osteoarthritis Syndrome SMAD3 SMAD3
Autosomal Dominant Polycystic Kidney Disease Ciliopathy PKD1/PKD2 Polycystin 1

Polycystin 2

Turner Syndrome Meiotic Error with Monosomy, Mosaicism, or De Novo Germ Cell Mutation 45X

45XO

Partial or Complete Absence of X Chromosome
Bicuspid Aortic Valve with TAA Neural Crest Migration NOTCH1 Notch 1
Familial TAA Smooth Muscle Contraction Proteins ACTA2 α-Smooth Muscle Actin
Familial TAA with Patent Ductus Arteriosus Smooth Muscle Contraction Proteins MYH11 Smooth Muscle Myosin
Familial TAA Smooth Muscle Contraction Proteins MYLK Myosin Light Chain Kinase
Familial TAA Smooth Muscle Contraction Proteins PRKG1 Protein Kinase c-GMP Dependent, type I
Loeys-Dietz Syndrome variants TGF-β Pathway TGF-βR1

TGF-βR2

SMAD3

TGF-β2

TGF-β3

These genetic diseases mostly affect either the synthesis of extracellular matrix protein or damage the smooth muscle cells both important component's of the aortic wall. Injury to any of these components lead to weakening of the aortic wall and dilation - resulting in aneurysm formation.

The aorta is the largest vessel of the body, but it is not homogenous. Its upper segment is composed by a larger proportion of elastin in comparison to collagen, therefore being more distensible. The lower segment has a larger proportion of collagen, therefore it is less distensible. It is also where most of the atherosclerotic plaques of the aorta are located.[1] Historically it was thought that abdominal and thoracic aortic aneurysms were caused by the same etiology: atherosclerotic degeneration of the aortic wall, but recently it has been theorized that they are indeed different diseases.[1]

The aortic arch mostly derives from the neural crest cell which differentiate into smooth muscle cells. These smooth muscle cells are probably more adapted to remodel the thoracic aorta and manage the higher pulse pressure and ejection volume due to increased production of elastic lamellae during development and growth.[1] The abdominal aorta remains with cells of mesodermal origin, which are more similar to that of the original primitive arterial. That difference results in the neural crest cell precursors of the thoracic aorta being able to respond differently to various cytokines and growth factors than the mesodermal precursors of the abdominal aorta,[7] such as homocysteine[8] and angiotensin II.[9]

When neural crest vascular smooth muscle cells are treated with TGF-β they demonstrate increased collagen production, while mesodermal vascular smooth muscle cell did not.[10] Not coincidently, mutations of the TGF-β receptor can cause thoracic aortic aneurysm but do not cause abdominal aortic ones.

The thoracic and abdominal aorta are very structurally different. While they both have three layers: intimal, medial and adventitia, the media of the thoracic aorta is comprised of approximately 60 units divided into vascular and avascular regions. The abdominal aorta consists of about 30 units and is entirely avascular, being dependent on trans-intimal diffusion of nutrients for its smooth muscle cells to survive.[11] It is believed that both differences explain why the abdominal aorta is more likely to form aneurysms.

The development of aortic aneurysms is defined by: inflammation: infiltration of the vessel wall by lymphocytes and macrophage; extracellular matrix damage: destruction of elastin and collagen by proteases (also metalloproteinases) in the media and adventitia; cellular damage: loss of smooth muscle cells with thinning of the media; and insufficient repair: neovascularization.[12]

Clinical Features

Thoracic aortic aneurysms: The aneurysms tend to grow slowly and most of them will never rupture. As they grow, however, their symptoms become more evident and present with mass effects over surrounding structures and pain. They may present with thoracic symptoms: interscapular or central pain, ripping chest pain and dyspnea. Atypical presentations include hoarseness, dizziness and dysphagia, due to esophageal compression.[13] Aneurysm rupture lead to massive internal bleeding, hypovolemic shock and it is usually fatal.

Abdominal aortic aneurysms: as the thoracic aneurysms, they begin asymptomatic but may cause symptoms as they grow and compress surrounding structures.[14]Even though they usually remain asymptomatic, when they rupture they present with an ensuing mortality of 85 to 90%., and symptomatic patients require urgent surgical repair.[15]

When symptomatic, abdominal aortic aneurysms present with:

  • Pain: in the chest, abdomen, lower back, or flanks. It may radiate to the groin, buttocks, or legs. The pain characteristics vary and may be deep, aching, gnawing, or throbbing It may also last for hours or days, not affected by movement. Occasionally, certain positions can be more comfortable and alleviate the symptoms;
  • Pulsating abdominal mass;
  • Ischemia: "cold foot" or a black or blue painful toe. This is usually the presentation when an aneurysm forms a blood cloth and it releases emboli to the lower extremities;
  • Fever or weight loss if caused by inflammatory states such as vasculitis.[14]

If ruptured, the abdominal aortic aneurysm can present with sharp abdominal pain, often radiating to the back, discoloration of the skin and mucosa, tachycardia and low blood pressure due to hypovolemic shock.

Differentiating Aortic Aneurysm from other Diseases

Thoracic aortic aneurysms: differential diagnosis include other causes of chest pain: acute aortic dissection, acute pericarditis, aortic regurgitation, heart failure, hypertensive emergencies, infective endocarditis, myocardial Infarction, pulmonary embolism, superior vena cava syndrome. [16]

Abdominal aortic aneurysms: differential diagnosis include causes of pulsatile abdominal mass and/or abdominal pain such as ruptured viscus, strangulated hernia, ruptured visceral artery aneurysms, mesenteric ischemia, acute cholecystitis, ruptured hepatobiliary cancer, acute pancreatitis, lymphomas, and diverticular abscess.[17]

These conditions can be easily differentiated using abdominal or thoracic imaging.

Epidemiology and Demographics

In the United States alone 15,000 people die yearly due to aortic aneurysms and it is the 13th leading cause of death. 1-2% of the population may have aortic aneurysms and prevalence rises up to 10% in older age groups. The disease varies according to where it takes place. In the thorax, the aortic arch is the less affected segment (10%) and the most common is the ascending aorta (50%). Regarding abdominal aneurysms, the infrarenal segment aortic aneurysms are three times more prevalent than the aortic aneurysms and dissections.[5]

Regarding other factors as age, abdominal aortic aneurysms usually present 10 years later than thoracic aortic aneurysms. Both lesions are more present in men, but the proportion is much higher regarding abdominal aortic aneurysms (6:1 male:female ratio) in comparison to thoracic ones.[5]

Abdominal aortic aneurysms also affect patients differently regarding race, as they are more prevalent among whites than blacks, asians and hispanics. It also seems to be declining in prevalence as evidenced by a Swedish study that found out a 2% prevalence of abdominal aortic aneurysms in comparison to earlier studies which reported 4-8%, probably due to risk-factor modification. [18]

Risk Factors

Many risk factors are common between both forms of aortic aneurysms, but some are specific for each presentation:

Natural History, Complications and Prognosis

Even though the majority of the aortic aneurysms remain asymptomatic for years, their natural history is dissection or rupture.[3] According to Laplace's law, as the aneurysms grow larger they have a higher rate of expansion. Due to that, the frequency of monitoring changes with the diameter of the abdominal aortic aneurysm, being every 3 years for aneurysms with a 3-3.4cm diameter, yearly for diameters of 3.5-4.4cm, and every 6 months for larger than 4.5cm.[18] For the thoracic one, up to 80% of the aneurysms will eventually rupture, and patients present with a 10-20% five-year survival rate if they remain untreated.[3] Risk of rupture doubles every 1cm in growth over the 5cm diameter in descending thoracic aorta.[20]

Besides rupturing and dissection of the aorta, aortic aneurysms can also present with systemic embolization and aortic regurgitation (if the thoracic aortic aneurysm is located in the ascending aorta). The altered blood flow in the aneurysm can also lead to the formation of blood cloths and embolization. [21]

Diagnosis

Diagnostic Criteria:

Thoracic aortic aneurysm: considered an aneurysm when the diameter is >4 cm.[2]

Abdominal aortic aneurysm: considered an aneurysm when the diameter is >3 cm.[22]

Symptoms:

Thoracic aortic aneurysm: as discussed above: most are asymptomatic. As they grow, they may cause: chest pain, dyspnea, hoarseness, dizziness, dysphagia and when they rupture: hypovolemic shock

Abdominal aortic aneurysm: begin asymptomatic but may cause pain, pulsating abdominal mass, peripheral ischemia, fever or weight loss. When they rupture, they cause acute abdominal pain and hypovolemic shock.

Laboratory Findings

  • There are no specific laboratory findings associated withaortic aneurysms.
  • Anemia can be seen in ruptured aortic aneurysms.

Imaging Findings

  • An abdominal ultrasound can be diagnostic of abdominal aortic aneurysms and is the imaging tool used to screen for aortic aortic aneurysms.
  • CTA/MRA can accurately demonstrate aortic aneurysms extent.

Other Diagnostic Studies

  • Conventional angiogram can be used to diagnose aortic aneurysms.

Treatment

Medical Therapy

Focus is to reduce systemic blood pressure, inhibit MMP (zinc endopeptidases that degrade the extracellular matrix in aortic aneurysms)[23], and contain the progression of atherosclerosis.

There are no established guidelines for this matter, treatment is still controversial and should be individualized.[24][25]

Surgery

Decision to perform elective surgery to prevent aneurysm rupture is complicated as there must be an appropriate patient selection and timing for repair of the aneurysm which demands selecting patients at the greatest risk of aneurysm rupture. Once rupture occurs, mortality is extremely high. Fatality rates of emergency surgical repair is 50% if the patient manages to reach the hospital, in comparison to 1-5% fatality rate in elective surgical repair.[26]

According to the 2005 AHA/ACC guidelines - it is recommended surgical repair of abdominal aortic aneurysms:

  • 5.5 cm in diameter or greater in asymptomatic patients;
  • Increase by 0.5 cm or greater in diameter in 6 months;
  • Symptomatic aneurysms.

Endovascular repair may be performed with better short-term morbidity and mortality rates but with failed long-term benefits over surgical repair. Endovascular is preferred in high-risk patients while surgical repair is generally indicated for low/average-risk patients.[26]

In thoracic aortic aneurysms, surgery is indicated in Marfan's syndrome when the aortic diameter reaches 5.0cm, or the rate of increase of the aortic root diameter approaches 1.0 cm per year, or progressive and severe aortic regurgitation. If family history is positive for aortic aneurysms, aggressive therapy may be indicated in individuals with Marfan and Loeys Dietz syndrome. Surgery consists in replacing the affected portion of the aorta. [25]

Prevention

Smoking cessation is an important measure to prevent aortic aneurysm progression and rupture, as is control of the other cardiovascular risks, such as hypertension, sedentarism and dyslipidemia.[17]

Related Chapters

References

  1. 1.0 1.1 1.2 1.3 Kuivaniemi, Helena, et al. "Understanding the pathogenesis of abdominal aortic aneurysms." Expert review of cardiovascular therapy 13.9 (2015): 975-987.
  2. 2.0 2.1 Radiopaedia - Thoracic Aortic Aneurysms - https://radiopaedia.org/articles/thoracic-aortic-aneurysm?lang=us accessed at 06/08/2020
  3. 3.0 3.1 3.2 Frederick, John R., and Y. Joseph Woo. "Thoracoabdominal aortic aneurysm." Annals of cardiothoracic surgery 1.3 (2012): 277.
  4. Livesay, James J., Gregory N. Messner, and William K. Vaughn. "Milestones in treatment of aortic aneurysm: Denton A. Cooley, MD, and the Texas Heart Institute." Texas Heart Institute Journal 32.2 (2005): 130.
  5. 5.0 5.1 5.2 Kuivaniemi, Helena, Chris D. Platsoucas, and M. David Tilson III. "Aortic aneurysms: an immune disease with a strong genetic component." Circulation 117.2 (2008): 242-252.
  6. Bhandari, R., Kanthi, Y. - The Genetics of Aortic Aneurysms - The American College of Cardiology - available at:https://www.acc.org/latest-in-cardiology/articles/2018/05/02/12/52/the-genetics-of-aortic-aneurysms accessed at 06/08/2020
  7. Ruddy JM, Jones JA, Ikonomidis JS. Pathophysiology of thoracic aortic aneurysm (TAA): is it not one uniform aorta? Role of embryologic origin. Progress in cardiovascular diseases. 2013;56(1):68–73.
  8. Steed MM, Tyagi SC. Mechanisms of cardiovascular remodeling in hyperhomocysteinemia. Antioxidants & redox signaling. 2011;15(7):1927–1943.
  9. Bruemmer D, Daugherty A, Lu H, Rateri DL. Relevance of angiotensin II-induced aortic pathologies in mice to human aortic aneurysms. Ann N Y Acad Sci. 2011;1245:7–10.
  10. Gadson PF, Jr, Dalton ML, Patterson E, et al. Differential response of mesoderm- and neural crest-derived smooth muscle to TGF-beta1: regulation of c-myb and alpha1 (I) procollagen genes. Experimental cell research. 1997;230(2):169–180.
  11. Wolinsky H, Glagov S. Comparison of abdominal and thoracic aortic medial structure in mammals. Deviation of man from the usual pattern. Circulation research. 1969;25(6):677–686.
  12. Ailawadi G, Eliason JL, Upchurch GR Jr. Current concepts in the pathogenesis of abdominal aortic aneurysm. J Vasc Surg 2003;38:584-8.
  13. Hiller, H. G., and N. R. F. Lagattolla. "Thoracic aortic aneurysm presenting with dysphagia: a fatal delay in diagnosis." Thoracic surgical science 4 (2007).
  14. 14.0 14.1 Abdominal Aortic Aneurysm (AAA) Symptoms - Stanford Healthcare https://stanfordhealthcare.org/medical-conditions/blood-heart-circulation/abdominal-aortic-aneurysm/symptoms.html - accessed at 06/08/2020
  15. Kent, K. Craig. "Abdominal aortic aneurysms." New England journal of medicine 371.22 (2014): 2101-2108.
  16. Thoracic Aneurysm Differential Diagnoses - Medscape available at: https://emedicine.medscape.com/article/761627-differential - accessed at 06/08/2020
  17. 17.0 17.1 17.2 Abdominal Aortic Aneurysm - Mayo Clinichttps://www.mayoclinic.org/diseases-conditions/abdominal-aortic-aneurysm/symptoms-causes/syc-20350688 - accessed at 06/08/2020
  18. 18.0 18.1 Ernst, Calvin B. "Abdominal aortic aneurysm." New England Journal of Medicine 328.16 (1993): 1167-1172.
  19. Thoracic Aortic Aneurysm - Mayo Clinic available at: https://www.mayoclinic.org/diseases-conditions/thoracic-aortic-aneurysm/symptoms-causes/syc-20350188 - accessed at 06/08/2020
  20. Juvonen T, Ergin MA, Galla JD, et al. Prospective study of the natural history of thoracic aortic aneurysms. Ann Thorac Surg 1997;63:1533-45
  21. Aortic Aneurysm: Symptoms and Complications - VeryWell Health available at: https://www.verywellhealth.com/aortic-aneurysm-symptoms-and-complications-4160769 - accessed at 06/08/2020
  22. Radiopaedia - Abdominal Aortic Aneurysms https://radiopaedia.org/articles/abdominal-aortic-aneurysm?lang=us Accessed at 06/08/2020
  23. 23.0 23.1 23.2 Danyi, Peter, John A. Elefteriades, and Ion S. Jovin. "Medical therapy of thoracic aortic aneurysms: are we there yet?." Circulation 124.13 (2011): 1469-1476.
  24. Yoshimura, Koichi, et al. "Current status and perspectives on pharmacologic therapy for abdominal aortic aneurysm." Current drug targets 19.11 (2018): 1265-1275.
  25. 25.0 25.1 Clift, Paul F., and Elena Cervi. "A review of thoracic aortic aneurysm disease." Echo Research and Practice 7.1 (2020): R1-R10.
  26. 26.0 26.1 Aggarwal, Sourabh, et al. "Abdominal aortic aneurysm: A comprehensive review." Experimental & Clinical Cardiology 16.1 (2011): 11.



Template:WikiDoc Sources Cardiology


Short QT Syndrome Overview

Short QT syndrome is a rare autosomal dominant inherited disease of the electrical conduction system of the heart. It is defined by short QT intervals (≤ 360 ms) that increases an individual propensity to atrial and ventricular tachyarrhythmias.[1] It occurs due to gain-of-function mutations in genes encoding for cardiac potassium channels KCNH2, KCNQ1 and KCNJ2. The shortened QT interval does not significantly change with heart rate, and there are tall and peaked T waves in the right precordium. It is associated with an increased risk of atrial fibrillation, syncope and sudden death.

Historical Perspective

The syndrome was first described by Dr. Prebe Bjerregaard MD, DMSc in 1999, who wrote the first clinical report of three members of one family who presented with persistently short QT interval.[2][3]

Classification

Pathophysiology

Short QT syndrome types 1-3 are due to increased activity of outward potassium currents in phase 2 and 3 of the cardiac action potential due to mutations in potassium channels. This causes a shortening of the plateau phase of the action potential (phase 2), causing a shortening of the overall action potential, leading to an overall shortening of refractory periods and the QT interval. In the families afflicted by short QT syndrome, two different missense mutations have been described in the human ether-a-go-go gene (HERG). These mutations result in expression of the same amino acid change in the cardiac IKr ion channel. This mutated IKr has increased activity compared to the normal ion channel, and would theoretically explain the above hypothesis. Short QT syndrome types 4 and 5 and 6 are due to mutations in the calcium channel and consequent reduction in L-type Ca-channel current.[8]

Genetics

In the families afflicted by short QT syndrome, mutations have been described in three genes, KvLQT1, the human ether-a-go-go gene (HERG), and KCNJ2. Mutations in the KCNH2, KCNJ2, and KCNQ1 genes cause short QT syndrome. These genes provide instructions for making proteins that act as channels across the cell membrane. These channels transport positively charged atoms (ions) of potassium into and out of cells. In cardiac muscle, these ion channels play critical roles in maintaining the heart's normal rhythm. Mutations in the KCNH2, KCNJ2, or KCNQ1 gene increase the activity of the channels, which changes the flow of potassium ions between cells. This disruption in ion transport alters the way the heart beats, leading to the abnormal heart rhythm characteristic of short QT syndrome. Short QT syndrome appears to have an autosomal dominant pattern of inheritance.

Due to the autosomal dominant inheritance pattern, individuals may have family members with a history of unexplained or sudden death at a young age (even in infancy), palpitations, or atrial fibrillation. The penetrance of symptoms is high in affected family members. It is also interesting to note that while mutations involving potassium channel genes associated with the long QT syndrome are loss-of-function mutations, the mutations that cause short QT syndrome are gain-of-function mutations.[9]

The calcium channels' dysfunction are mostly due to CACNA1C and CACNB2b genes mutation which caused Brugada-like ECG changes with short QT interval. Lastly, a novel mutation of the CACNA2D1 gene was reported in a 17-year-old female who presented with short QT interval and ventricular fibrillation.[9]

Causes

The causes of shortening of the QT interval can be divided into primary causes (Short QT syndrome types 1-5) and secondary causes such as drugs and electrolyte disturbances.

Common Causes

Causes in Alphabetical Order

Differentiating Short QT Syndrome from other Disorders

Short QT may have secondary causes that must be ruled out, since the short QT syndrome is by definition a primary, congenital disease of the heart. Such causes include: hyperkalemia, hypercalcemia, acidosis, hyperthermia - caused by the use of drugs like digitalis, effect of acetylcholine or catecholamine and activation of Katp or Kach current.[1] Only after ruling out such causes is that the diagnosis of short QT syndrome may be made.

Epidemiology and Demographics

European studies have estimated a prevalence of 0.02% to 0.1% among adults. A paper from 2015 which tried to assess the prevalence among pediatric population in the U.S. estimated a prevalence of 0.05% at this population.[10] Sudden cardiac arrest has a peak incidence between the second and fourth decades of life, which might indicate an association with testosterone levels in males.[9]

Natural History, Complications, Prognosis

The disease can have clinical manifestations from the first year of life until as late as 80 years old, and most cases are symptomatic.[9] Its most frequent symptoms include cardiac arrest (which was the first symptom in 28% of the patients), followed by palpitations, and syncope. Patients may also present with atrial fibrillation and ventricular extrasystoles. They remain at high risk for sudden death during their lifetime and may present with a strong family history for this occurence.[9] Sudden cardiac death presents with two high-risk peaks, one in the first year of life, and another one from 20 to 40 years old.[11] Even though familial association is present in the majority of patients, the yields for genetic tests is low.[9]

Screening

Since the disease is so rare, no screening for the general population is advised. Individuals with short QT interval detected on the ECG must first rule out other causes. Genetic screening is performed if a patient presents with: sudden cardiac arrest, history of polymorphic ventricular tachycardia or ventricular fibrillation without a known cause, history of unexplained syncope, young individuals with atrial fibrillation, family members diagnosed with short QT syndrome, family members who died from sudden cardiac arrest.[12]

Diagnosis

The first step for diagnosing short QT syndrome is ruling out secondary causes, such as the ones cited above.[1] Once them are ruled out, there are two suggested diagnostic approaches in the medical literature: one proposed by GOLLOB, and another one proposed by PRIORI:


- Scoring type of diagnostic criteria, as proposed by the Arrhythmia Research Laboratory at the University of Ottawa Heart Institute from Drs. Michael H Gollob and Jason D Roberts.[13]

Diagnostic Criteria for Short QT Syndrome from UoO Heart Institute
QTc in milliseconds
  • <370 = 1 point
  • <350 = 2 points
  • <330 = 3 points
J point - T peak interval in milliseconds
  • <120 = 1 point
Clinical History
Family History
  • 1st or 2nd degree relative with SQTS = 2 points
  • 1st or 2nd degree relative with sudden death = 1 point
  • Sudden infant death syndrome = 1 point
Genotype
  • Genotype positive = 2 points
  • Mutation of undetermined significance in a culprit gene = 1 point

The points are summed and interpreted as follows:

  • > or equal to 4 points: High-probability of SQTS
  • 3 Points: Intermediate probability of SQTS
  • 2 points or less: Low probability of SQTS

- Diagnostic criteria suggested by PRIORI, 2015 for the European Society of Cardiology:

  • QTc <340ms or QTc <360ms and one or more of the following:
    • Confirmed pathogenic mutation;
    • Family history of SQTS;
    • Family history of sudden death at 40 years of age;
    • Survival from a VT/VF episode at the absence of heart diseases.[14]

Electrocardiogam

Duration of the QT Interval

Tall peaked T wave and short QT in the right precordial lead V2

While the QT interval is generally short, the QT interval alone cannot be used to distinguish the patient with short QT syndrome from a normal patient (similar to long QT syndrome).[15] In general though, if the QTc is < 330 msec in a male, and <340 msec in a female, then short QT syndrome can be diagnosed even in the absence of symptoms as these QT intervals are much shorter than in the rest of the population. On the other hand, if the QTc is moderately shortened to < 360 msec in a male or < 370 msec in a female, the short QT syndrome should only be diagnosed in the presence of symptoms or a family history according to the guidelines above. [14][13]

SQTS 1,2,3

The QTc is usually < 300-320 msec.[4][5][6]

SQTS 4,5,6

The QTc is usually just under 360 msec [16]

Variability of the QT Interval with Heart Rate

The short QT interval does not vary significantly with the heart rate. Normally the QT will become longer at slow heart rates and this does not occur among patients with short QT syndrome. The Bazett formula may overcorrect (i.e. shorten) the QT interval in the patient with bradycardia, and it is therefore important to use treadmill testing to increase the heart rate and confirm the absence of QT interval variation.[17]

Other ECG findings:

  • There is a high prevalence of early depolarization patterns on SQTS.[8]
  • QRS complex is followed by T wave without any ST segment.[9]
  • Prominent U wave separated by isoelectric T-U segment.[9]
  • Longer Tpeak - Tend interval.[9]
  • Prolongation of the QT interval at slower heart rates is suppressed, remaining below the lower limit.[9]
  • Depressed PQ segment commonly observed in the inferior and anterior leads.[9]
  • In a very limited number of patients it has been observed that early repolarization (which is present in 65% of patients with SQTS) and a longer T wave peak to T wave end period is associated with the occurrence of arrhythmic events.[18]

70% of patients with short QT have a history of either paroxysmal atrial fibrillation or permanent atrial fibrillation, and atrial fibrillation is the first sign of short QT syndrome in 50% of patients. In young patients with lone atrial fibrillation, the patient should be screened for short QT syndrome.

Electrophysiologic Studies

Among patients with SQTS, the atrial and ventricular refractory periods are shortened (ranging from 120 to 180 ms). Ventricular fibrillation can be induced on programmed stimulation in 90% of patients with short QT syndrome. Despite the high rate of VF inducibility, the risk of sudden death in an individual patient is difficult to predict given the genetic and clinical heterogeneity of short QT syndrome and the limited number of patients with short follow-up to date. The limitations of electrophysiologic testing are highlighted by a study of Giustetto et al in which the sensitivity of electrophysiologic testing in relation to the clinical occurrence of ventricular fibrillation was only 50% (3 of 6 cases)[19]. Importantly, lack of inducibility does not exclude a future episode of ventricular fibrillation[20]. Thus, the role of electrophysiologic testing in risk stratification of the patient with SQTS is not clear at present.

Genetic Testing

Because new genetic variants of SQTS are still being identified, a negative genetic test for existing variants does not exclude the presence of SQTS. A negative genetic test for existing variants could mean that a patient with a short QT interval does not have a heretofore unidentified variant of SQTS.

However, among family members of an affected patient, genetic testing may identify the syndrome in an asymptomatic patient, and may also rule out the presence of the syndrome in asymptomatic patients.

Mutations in the KCNH2, KCNJ2, and KCNQ1 genes cause short QT syndrome. These genes provide instructions for making proteins that act as channels across the cell membrane. These channels transport positively charged atoms (ions) of potassium into and out of cells. In cardiac muscle, these ion channels play critical roles in maintaining the heart's normal rhythm. Mutations in the KCNH2, KCNJ2, or KCNQ1 gene increase the activity of the channels, which changes the flow of potassium ions between cells. This disruption in ion transport alters the way the heart beats, leading to the abnormal heart rhythm characteristic of short QT syndrome. Short QT syndrome appears to have an autosomal dominant pattern of inheritance.

Centers Performing Genetic Testing for Short QT Syndrome

Treatment

Device Based Therapy

An implantable cardioverter-defibrillator (ICD) is indicated in symptomatic patients who have either survived a sudden cardiac arrest and/or have had documented episodes of spontaneous sustained ventricular tachyarrhythmias with or without syncope. There's a problem with ICD in such patients though, because the tall and peaked T wave can be interpreted as a short R-R interval provoking inappropriate shock.[9]

Generally accepted criteria for implantation of an AICD also include:

  • Inducibility on electrophysiologic testing;
  • Positive genetic test, although a negative result does not exclude the presence of a previously unreported mutation or the occurrence of a future arrhythmic event.

Complications of AICD Placement

Inappropriate shocks may be delivered due to[21]:

Pharmacologic Therapy

Short QT Syndrome 1 (SQT1)

The efficacy of pharmacotherapy in preventing ventricular fibrillation has only been studies in patients with SQT1. Given the limited number of patients studied, and the limited duration of follow-up, pharmacotherapy as primary or secondary preventive therapy for patients with SQT1 cannot be recommended at this time. AICD implantation remains the mainstay of therapy in these patients. Pharmacotherapy may play an adjunctive role in reducing the risk of events in patients with an AICD as described below in the indications section.

Patients with Short QT Syndrome 1 (SQT1) have a mutation in KCNH2 (HERG). Class IC and III antiarrhythmic drugs do not produce any significant QT interval prolongation [22][23] . Flecainide has not been shown to consistently reduce the inducibility of ventricular fibrillation.[24] Although it does not prolong the QT interval in SQT1 patients, propafenone reduces the risk of recurrent atrial fibrillation in SQT1 patients.[25]

Quinidine in contrast may be effective in patients with SQT1 in so far as it blocks both potassium channels (IKr, IKs, Ito, IKATP and IK1) and the inward sodium and calcium channels. In four out of four patients, Quinidine prolonged the QT interval from 263 +/- 12 msec to 362 +/-25 msec, most likely due to its effects on prolonging the action potential and by virtue of its action on the IK channels. Although Quinidine was successful in preventing the inducibility of ventricular fibrillation in 4 out of 4 patients, it is unclear if the prolongation of the QT interval by quinidine would reduce the risk of sudden cardiac death. It also prolonged the ST interval and T wave durations, restored the heart rate dependent variability in the QT interval and decreased depolarization dispersion in patients with SQT1.

There is a report which states that disopyramide was also effectively used in two patients with SQT-1, increasing their QT interval and ventricular refractory period while also abbreviating the Tpeak-Tend interval.

As atrial fibrillation is also very commonly found on those patients propafenone has also been successfully used to prevent its paroxysms, without having any effect on QT interval.[9]

Although pharmacotherapy can be used to suppress the occurrence of atrial fibrillation in patients with SQT1, AICD implantation is the mainstay of therapy, and pharmacotherapy to prevent sudden death should is only indicated if AICD implantation is not possible.

Indications for Pharmacologic Therapy

The following are indications for pharmacologic therapy of SQTS[26]:

  • In children as an alternate to AICD implantation;
  • In patients with a contraindications AICD implantation;
  • In patients who decline AICD implantation;
  • In patients with appropriate AICD discharges to reduce the frequency of discharges;
  • In patients with atrial fibrillation to reduce the frequency of symptomatic episodes.

References

  1. 1.0 1.1 1.2 Patel, Chinmay, Gan-Xin Yan, and Charles Antzelevitch. "Short QT syndrome: from bench to bedside." Circulation: Arrhythmia and Electrophysiology 3.4 (2010): 401-408. Available at https://doi.org/10.1161/CIRCEP.109.921056
  2. Gussak I, Brugada P, Brugada J, Wright RS, Kopecky SL, Chaitman BR, Bjerregaard P (2000). "Idiopathic short QT interval: a new clinical syndrome?". Cardiology. 94 (2): 99–102. doi:47299 Check |doi= value (help). PMID 11173780. Retrieved 2012-09-03.
  3. http://www.shortqtsyndrome.org/short_qt_history.htm
  4. 4.0 4.1 Brugada R, Hong K, Dumaine R, Cordeiro J, Gaita F, Borggrefe M, Menendez TM, Brugada J, Pollevick GD, Wolpert C, Burashnikov E, Matsuo K, Wu YS, Guerchicoff A, Bianchi F, Giustetto C, Schimpf R, Brugada P, Antzelevitch C (2004). "Sudden death associated with short-QT syndrome linked to mutations in HERG". Circulation. 109 (1): 30–5. doi:10.1161/01.CIR.0000109482.92774.3A. PMID 14676148. Retrieved 2012-09-02. Unknown parameter |month= ignored (help)
  5. 5.0 5.1 Bellocq C, van Ginneken AC, Bezzina CR, Alders M, Escande D, Mannens MM, Baró I, Wilde AA (2004). "Mutation in the KCNQ1 gene leading to the short QT-interval syndrome". Circulation. 109 (20): 2394–7. doi:10.1161/01.CIR.0000130409.72142.FE. PMID 15159330. Retrieved 2012-09-02. Unknown parameter |month= ignored (help)
  6. 6.0 6.1 Priori SG, Pandit SV, Rivolta I, Berenfeld O, Ronchetti E, Dhamoon A, Napolitano C, Anumonwo J, di Barletta MR, Gudapakkam S, Bosi G, Stramba-Badiale M, Jalife J (2005). "A novel form of short QT syndrome (SQT3) is caused by a mutation in the KCNJ2 gene". Circulation Research. 96 (7): 800–7. doi:10.1161/01.RES.0000162101.76263.8c. PMID 15761194. Retrieved 2012-09-02. Unknown parameter |month= ignored (help)
  7. Templin, Christian, et al. "Identification of a novel loss-of-function calcium channel gene mutation in short QT syndrome (SQTS6)." European heart journal 32.9 (2011): 1077-1088.
  8. 8.0 8.1 Ossama K. Abou Hassan, MD (10/05/2016). "Short QT Syndrome". American College of Cardiology. Check date values in: |date= (help)
  9. 9.00 9.01 9.02 9.03 9.04 9.05 9.06 9.07 9.08 9.09 9.10 9.11 9.12 Rudic, Boris, Rainer Schimpf, and Martin Borggrefe. "Short QT syndrome–review of diagnosis and treatment." Arrhythmia & electrophysiology review 3.2 (2014): 76.
  10. Guerrier, Karine, et al. "Short QT interval prevalence and clinical outcomes in a pediatric population." Circulation: Arrhythmia and Electrophysiology 8.6 (2015): 1460-1464.
  11. Campuzano, Oscar, et al. "Recent advances in short QT syndrome." Frontiers in cardiovascular medicine 5 (2018): 149.
  12. "Short QT Syndrome: Diagnosis and Tests". Cleveland Clinic. 19/05/2020. Check date values in: |date= (help)
  13. 13.0 13.1 Gollob M, Redpath C, Roberts J. (2011). "The Short QT syndrome: Proposed Diagnostic Criteria". J Am Coll Cardiol. 57 (7): 802–812. doi:10.1016/j.jacc.2010.09.048. PMID 21310316.
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