Sandbox Jose

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. 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.

• Acute coronary syndromes
• Aortic dissection
• Pulmonary embolism

Differentiating heartburn from angina

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

• Gastroesophageal reflux disease (GERD)
• Eosinophillic esophagitis
• Malignancy
• Achalasia
• Peptic ulcer disease

Diagnosis

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

The diagnosis of GERD is made based on:

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

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.

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

• High Risk: Men >50 years with chronic gastroesophageal reflux disease symptoms (>5 years), AND:
  • Nocturnal reflux symptoms,
  • Hiatal hernia,
  • Elevated body mass index,
  • Tobacco use,
  • Intra-abdominal distribution of fat.

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.

Screening for H. Pylori is not recommended routinely on GERD.

Diagnostic Testing for GERD

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.

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.

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

Template:WikiDoc Sources

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

• Peripheral arterial disease
• Venous claudication
• Arterial thromboembolism
• Cholesterol embolism
• Vasculitis
• Nerve root compression (radiculopathy, plexopathy)
• Peripheral neuropathy
• Lumbar canal stenosis (pseudoclaudication)
• Spinal stenosis
• Arthritis/Connective tissue disease
• Baker's cyst
• Muscle strain
• Ligament/tendon injury
• Chronic compartment syndrome

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

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.
• 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.
• In patients with claudication, supervised exercise programs increases functional status and reduce leg symptoms.
• 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.

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.
• 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.
• Anticoagulation should not be used to reduce the risk of cardiovascular ischemic events in patients with PAD.
• Pentoxifylline is not effective for treatment of claudication.

References

Template:WikiDoc Sources

Resident Survival Guide
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Emergency Medicine Chapters - Internal Medicine Related

Intended Chapter - Available Chapter	Resident Survival Guide	Chapter Status
Shock - Shock
Sepsis - Sepsis
Coma and Altered Mental Status - Coma
Anaphylaxis and allergies - Anaphylaxis
Delirium - Delirium
Sedation and analgesia - Sedation / Analgesic
Pain Management - Pain
Airway Management - Intubation
Cardiac Arrest - Sudden cardiac death#Cardiac Arrest as a Subtype of Sudden Death
Acute Respiratory Insufficiency - Respiratory failure
Fever - Fever
Hypothermia - Hypothermia
Dyspnea - Dyspnea
Chest Pain - Chest pain
Syncope - Syncope
Nausea and Vomiting - Nausea and vomiting
Hemoptysis - Hemoptysis
Acute Diarrhea - Diarrhea
Jaundice - Jaundice
Abdominal Pain - Abdominal pain
Headache - Headache
Ascitis - Ascites
Lumbar Pain - Low back pain
STEMI - ST elevation myocardial infarction
NSTEMI - Unstable angina / non ST elevation myocardial infarction
Atrial Fibrillation - Atrial fibrillation
Tachyarrhythmias - Tachyarrhythmia
Bradycardia - Bradycardia
Acute Heart Failure - Congestive heart failure
Hypertensive Emergencies - Hypertensive crisis
Acute Aortic Syndromes - Aortic dissection / Aortic aneurysm
Acute Pericarditis - Pericarditis
Cardiac Tamponade - Cardiac tamponade
Acute Myocarditis - Myocarditis
Infectious Endocarditis - Endocarditis
Deep Vein Thrombosis - Deep vein thrombosis
Acute Arterial Occlusion - Thromboembolism
Asthma - Asthma
CPOD - Chronic obstructive pulmonary disease
Community-acquired Pneumonia - Pneumonia
Pulmonary Abscess - Lung abscess
Pneumonitis - Pneumonitis
Alveolar Hemorrhage - Pulmonary hemorrhage
Pleural Effusion - Pleural effusion
Pulmonary Thromboembolism - Pulmonary embolism
Pneumothorax - Pneumothorax
Upper Airway Infections -
HIV - Human Immunodeficiency Virus (HIV)
Influenza - Influenza
Urinary Tract Infections - Urinary tract infection
Dengue Fever - Dengue fever
Leptospirosis - Leptospirosis
Rocky Mountain Spotted Fever - Rocky Mountain spotted fever
Typhus - Typhus
Hemorrhagic Fever - Viral hemorrhagic fever
Tetanus - Tetanus
Chikungunya - Chikungunya
Zika Virus Disease - Zika virus infection
Yellow Fever - Yellow fever
Ebola - Ebola
Stroke - Stroke
Subarachnoid Hemorrhage - Subarachnoid hemorrhage
Intraparenquimatous Intracranial Hemorrhage Intracranial hemorrhage		NEEDS WORK
CNS Infections - Encephalitis / Meningitis		NOT MICROCHAPTER STRUCTURE
Acute Flaccid Paralysis - Flaccid paralysis		NOT MICROCHAPTER STRUCTURE
Seizures - Seizure
Vertigo - Vertigo
Politrauma - Polytrauma		NEEDS REWORKING
Hepatic Encephalopathy - Hepatic encephalopathy
Hepatorenal Syndrome - Hepatorenal syndrome
Upper Digestive Hemorrhage - Upper gastrointestinal bleeding
Lower Digestive Hemorrhage - Lower gastrointestinal bleeding
Spontaneous Bacterial Peritonitis - Spontaneous bacterial peritonitis
Secondary Peritonitis - Secondary peritonitis
Hepatic Failure - Hepatic failure
Hepatitis - Hepatitis
Acute Diverticulitis - Diverticulitis
Acute Pancreatitis - Acute pancreatitis
Acute Renal Injury - Acute kidney injury
Rhabdomyolisis - Rhabdomyolysis
Acid-base Disorders - Acidosis / Alkalosis		NEEDS DIAGNOSTIC APPROACH
Hyponatremia - Hyponatremia
Hypernateremia - Hypernatremia
Hypokalemia - Hypokalemia
Hyperkalemia - Hyperkalemia
Hypocalcemia - Hypocalcemia
Hypercalcemia - Hypercalcemia
Ureterolithiasis - Kidney stone		PROBLEM SEARCHING FOR THE MEDICAL TERM - KEYWORD
Hypoglycemia - Hypoglycemia
Hyperglycemias - Hyperglycemia
Thyreotoxic Crisis - Thyroid storm
Mixedema Coma - Myxedema coma
Adrenal Insufficiency - Adrenal insufficiency
Acute Monoarthritis - Monoarthritis
Vasculitis - Vasculitis / Behçet's Behçet's disease / Antiphospholipid Syndrome Antiphospholipid syndrome / Sclerodermic Renal Crisis / Erythema Nodosum Erythema nodosum		Sclerodermic renal crisis not AVAILABLE
Septic Arthritis - Septic arthritis
Gout - Gout
Coagulhopaties -Coagulopathy		NEEDS REWORKING
Bleeding - Bleeding
Sickle Cell Disease - Sickle-cell disease
Febrile Neutropenia - Febrile neutropenia
Acute Transfusional Reactions - Transfusion reaction
Thrombocytopenia - Thrombocytopenia
Oncologic Emergencies - Tumor Lysis Syndrome - Tumor lysis syndrome
Exogenous Intoxications - Intoxication		NEEDS REWORKING
Drowning - Drowning
Alcohol Withdraw Syndrome - Alcohol withdrawal
Poisonous Animals-related Accidents		NOT AVAILABLE
Pharmacodermias - Stevens-Johnson syndrome / Toxic epidermal necrolysis
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 (...)
Urticaria Urticaria and Angioedema Angioedema		Angioedema NOT ON MICROCHAPTER
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		Bartholin's not available - abscess Foreign bodies not available Vulvar trauma not available Sexual Violence may need REWORK
Obstetric Emergencies: 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		Abortion not available Preterm not available Dystocia not available Classification not available on Eclampsia
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;		Periorbital Cellulits Endophthalmitis and Glaucoma not on microchapters Intraocular hemorrhage not accurately depicting intraocular hemorrhage Others not present
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		Amigdalitis - not present Pharyngitis - needs removing definition
Surgical Emergencies -
Psychiatric Emergencies -

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

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

	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

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. 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.

• Acute coronary syndromes
• Aortic dissection
• Pulmonary embolism

Differentiating heartburn from angina

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

• Gastroesophageal reflux disease (GERD)
• Eosinophillic esophagitis
• Malignancy
• Achalasia
• Peptic ulcer disease

Diagnosis

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

The diagnosis of GERD is made based on:

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

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.

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

• High Risk: Men >50 years with chronic gastroesophageal reflux disease symptoms (>5 years), AND:
  • Nocturnal reflux symptoms,
  • Hiatal hernia,
  • Elevated body mass index,
  • Tobacco use,
  • Intra-abdominal distribution of fat.

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.

Screening for H. Pylori is not recommended routinely on GERD.

Diagnostic Testing for GERD

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.

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.

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

Template:WikiDoc Sources

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

• Peripheral arterial disease
• Venous claudication
• Arterial thromboembolism
• Cholesterol embolism
• Vasculitis
• Nerve root compression (radiculopathy, plexopathy)
• Peripheral neuropathy
• Lumbar canal stenosis (pseudoclaudication)
• Spinal stenosis
• Arthritis/Connective tissue disease
• Baker's cyst
• Muscle strain
• Ligament/tendon injury
• Chronic compartment syndrome

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

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.
• 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.
• In patients with claudication, supervised exercise programs increases functional status and reduce leg symptoms.
• 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.

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.
• 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.
• Anticoagulation should not be used to reduce the risk of cardiovascular ischemic events in patients with PAD.
• Pentoxifylline is not effective for treatment of claudication.

References

Template:WikiDoc Sources

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;
• 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;
• 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.

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.
• 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.

Differentiating Any Disease from other disease

• Children who met criteria for COVID-19-associated multisystem inflammatory syndrome presented features that overlapped with the ones seen on Kawasaki's disease and toxic shock syndrome, such as conjunctival injection, oropharyngeal findings (red and/or cracked lips, strawberry tongue), rash, swollen and/or erythematous hands and feet, and cervical lymphadenopathy.
• PCR tests for SARS-CoV-2 were positive in the minority of cases (26%), while the IgG antibody was positive in most patients (87%) and it remains as the preferred laboratory test for differentiating such diseases;
• The first cases of COVID-19-associated multisystem inflammatory syndrome presented with: unrelenting fever (38–40°C), conjunctivitis, cutaneous rash, peripheral edema, extremity pain and remarkable gastrointestinal symptoms. Most didn't have any respiratory symptoms, and all progressed to warm vasoplegic shock, refractory to volume resuscitation demanding vasopressors for hemodynamic support.
• Serum IL-6 level was elevated in most patients. IL-2R, IL-18, and CXCL 9 levels were elevated in all patients of a cohort and mildly increased IFN-γ and IL-8 levels in some.
• TNF-α, IL-1b, IL-2, IL-4, IL-5, and IL-13 levels remained normal in one in a series of cases from New York City.

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

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)	-

• Most patients presented with the following findings: elevated erythrocyte sedimentation rate or C-reactive protein level, elevated ferritin level, lymphocytopenia, hypoalbuminemia, neutrophilia, elevated alanine aminotransferase level, anemia, thrombocytopenia prolonged INR, elevated d-dimer level, or elevated fibrinogen level.

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.
• The median age found out in a study published by JAMA was 9 years.

Gender

• Most of the cases, estimated in two thirds, seem to happen in boys.

Race

• It seems to affect predominantly blacks and asians.

Comorbidities

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

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-
  • 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).
• It is also suspected that since MIS-C presents predominantly with gastrointestinal manifestations, it replicates predominantly in the gastrointestinal tract.

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.
• The mortality rate among 186 children with MIS-C was 2%.

Age

• Among the 186 children with MIS-C distribution of age group was
  • <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.
  • 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.

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

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

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;
• 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;
• 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.

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.
• 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.

Differentiating Any Disease from other disease

• Children who met criteria for COVID-19-associated multisystem inflammatory syndrome presented features that overlapped with the ones seen on Kawasaki's disease and toxic shock syndrome, such as conjunctival injection, oropharyngeal findings (red and/or cracked lips, strawberry tongue), rash, swollen and/or erythematous hands and feet, and cervical lymphadenopathy.
• PCR tests for SARS-CoV-2 were positive in the minority of cases (26%), while the IgG antibody was positive in most patients (87%) and it remains as the preferred laboratory test for differentiating such diseases;
• The first cases of COVID-19-associated multisystem inflammatory syndrome presented with: unrelenting fever (38–40°C), conjunctivitis, cutaneous rash, peripheral edema, extremity pain and remarkable gastrointestinal symptoms. Most didn't have any respiratory symptoms, and all progressed to warm vasoplegic shock, refractory to volume resuscitation demanding vasopressors for hemodynamic support.
• Serum IL-6 level was elevated in most patients. IL-2R, IL-18, and CXCL 9 levels were elevated in all patients of a cohort and mildly increased IFN-γ and IL-8 levels in some.
• TNF-α, IL-1b, IL-2, IL-4, IL-5, and IL-13 levels remained normal in one in a series of cases from New York City.

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

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)	-

• Most patients presented with the following findings: elevated erythrocyte sedimentation rate or C-reactive protein level, elevated ferritin level, lymphocytopenia, hypoalbuminemia, neutrophilia, elevated alanine aminotransferase level, anemia, thrombocytopenia prolonged INR, elevated d-dimer level, or elevated fibrinogen level.

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.
• The median age found out in a study published by JAMA was 9 years.

Gender

• Most of the cases, estimated in two thirds, seem to happen in boys.

Race

• It seems to affect predominantly blacks and asians.

Comorbidities

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

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-
  • 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).
• It is also suspected that since MIS-C presents predominantly with gastrointestinal manifestations, it replicates predominantly in the gastrointestinal tract.

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.
• The mortality rate among 186 children with MIS-C was 2%.

Age

• Among the 186 children with MIS-C distribution of age group was
  • <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.
  • 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.

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

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

External links

Classification	[[d: |D]] ICD-10: Q85.1 ICD-9-CM: 759.5 OMIM: 191100 613254 DiseasesDB: 13433
External resources	MedlinePlus: 000787 eMedicine: neuro/386 derm/438 ped/2796 radio/723 Patient UK: Sandbox Jose NCI: Sandbox Jose GeneReviews: Tuberous Sclerosis Complex Orphanet: 805

• tuberous-sclerosis at NIH/UW GeneTests
• GeneReview/NCBI/NIH/UW entry on Tuberous Sclerosis Complex

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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).

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). 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.

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. Diagnosed mostly during early adulthood, may cause pneumothorax. Multifocal micronodular pneumocyte hyperplasia can occur in both men and women and are mostly asymptomatic.

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

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.

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. 80% of children under two-years-old with TSC have at least one rhabdomyoma, and about 90% of those will have several.

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. 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

Major Features
	Location	Sign	Onset	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.

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),hypomelanotic macules, shagreen patches, and forehead plaques.

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).

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.

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.

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.

• 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:

• 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.  Everolimus also showed evidence of effectiveness at treating epilepsy in some people with TSC. In 2017, the European Commission approved everolimus for treatment of refractory partial-onset seizures associated with TSC.

Neurosurgical intervention may reduce the severity and frequency of seizures in TSC patients. 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.

Other treatments that have been used to treat TSC manifestations and symptoms include a ketogenic diet for intractable epilepsy and pulmonary rehabilitation for LAM. 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.

External links

Classification	[[d: |D]] ICD-10: Q85.1 ICD-9-CM: 759.5 OMIM: 191100 613254 DiseasesDB: 13433
External resources	MedlinePlus: 000787 eMedicine: neuro/386 derm/438 ped/2796 radio/723 Patient UK: Sandbox Jose NCI: Sandbox Jose GeneReviews: Tuberous Sclerosis Complex Orphanet: 805

• tuberous-sclerosis at NIH/UW GeneTests
• GeneReview/NCBI/NIH/UW entry on Tuberous Sclerosis Complex

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

Syncope classification

Vasovagal

Micturation

cough

xxxx

KKKKKKK

yyyyy

Case courtesy of Dr Vinay V Belaval, Radiopaedia.org, rID: 66974

Disease	Type	Sign		Symptom

Syncope is classified into three categories:

• Neurally mediated
• Cardiac
• Vasovagal

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

Resident Survival Guide

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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 or >4 cm if thoracic, 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.

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.

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. The genetic alterations associated with these genetic syndromes are the following:

Genetic diseases associated with aortic aneurysms

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. 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.

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. 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, such as homocysteine and angiotensin II.

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. 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. 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.

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. 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.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.

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.

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.

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.

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.

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.

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.

Risk Factors

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

• Abdominal aortic aneurysm: smoking, male gender, age (>65 years), race (white), family history, other aneurysms.
• Thoracic aortic aneurysm: smoking, age (>65 years), hypertension, atherosclerosis, family history, Marfan's syndrome, bicuspid aortic valve.

Natural History, Complications and Prognosis

Even though the majority of the aortic aneurysms remain asymptomatic for years, their natural history is dissection or rupture. 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. 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. Risk of rupture doubles every 1cm in growth over the 5cm diameter in descending thoracic aorta.

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.

Diagnosis

Diagnostic Criteria:

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

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

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), and contain the progression of atherosclerosis.

• Beta-blockers may help in reducing the rate of expansion of the aortic aneurysm, reducing shear stress - studies have been mostly on Marfan patients and they found a low compliance with propranolol due to a significant effect on quality of life;
• Tetracyclines inhibit the MMP endopeptidases, and has been used in conditions in which MMP are overexpressed such as rheumatoid arthritis. There are studies in humans showing that doxycycline reduced the rate of expansion of aortic aneurysms. Roxithromycin, a macrolide has been also show to reduce the expansion of the aortic aneurysms.
• Statins may also be helpful due to their pleiotropic effecs, reducing the oxidative stress by blocking the reactive oxygen species on aneurysms, suppressing the NADH/NADPH oxidase system.
• Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers promotes vascular hypertrophy, cell proliferation and production of extracellular matrix. It also activates the NADH/NADPH oxidase system, both stimulating and inhibiting MMPs and degradation of extracellular matrix. There is a controversy of which class is more effective, and ongoing trials are being run to further clarify these questions.

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

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.

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.

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.

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.

Related Chapters

• Aortic Dissection
• Thoracic Aortic Aneurysm
• Abdominal Aortic Aneurysm
• Aneurysm

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. 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.

Classification

• Short QT syndrome type 1 (SQT1): This variant is due to a gain-of-function mutation of the rapid component of the delayed rectifier potassium current HERG (KCNH2) channel(IKr). The variant is a result of missense mutations which increase IKr. It is associated with sudden death and sudden infant death syndrome.
• Short QT syndrome type 2 (SQT2): Caused by a mutation in the KCNQ1 gene. In the first patient, a g919c substitution in the KCNQ1 gene encoding for the K+ channel KvLQT1 was identified. The mutation led to a gain of function in in the KvLQT1 (I(Ks)) channel. This variant is associated with ventricular fibrillation.
• Short QT syndrome type 3 (SQT3): This variant results from a G514A substitution in the KCNJ2 gene ( a change from aspartic acid to asparagine at position 172 (D172N)). This causes a defect in the gene coding for the inwardly rectifying Kir2.1 (I(K1)) channel. The ECG shows asymmetrical T waves. These patients have an increased risk for re-entry arrhythmias.
• Short QT syndrome type 4 (SQT4): A loss of function mutation in the CACNA1C gene alters the encoding for the α1- and β2b-subunits of the L-type calcium channel. The phenotype is similar to Brugada syndrome combined with a short QT interval. There is an increased risk of sudden cardiac death.
• Short QT syndrome type 5 (SQT5): A loss of function mutation in the CACNB2B gene alters the encoding for the α1- and β2b-subunits of the L-type calcium channel. The phenotype is similar to Brugada syndrome combined with a short QT interval. There is an increased risk of sudden cardiac death.
• Short QT syndrome type 6 (SQT6): A loss of function mutation in the CACNAD2D1 coding for the Cavα2δ-1 subunit of the L-type calcium channel.

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 I_Kr ion channel. This mutated I_Kr 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.

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.

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.

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

• Hypercalcemia
• Digoxin

Causes in Alphabetical Order

• Acidosis
• Altered autonomic tone
• Digoxin
• Hypercalcaemia
• Hyperkalemia
• Hyperthermia
• Lanatoside C
• Rufinamide
• Short QT syndrome type 1
• Short QT syndrome type 2
• Short QT syndrome type 3
• Short QT syndrome type 4
• Short QT syndrome type 5
• Short QT syndrome type 6

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. 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. 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.

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. 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. 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. Even though familial association is present in the majority of patients, the yields for genetic tests is low.

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.

Diagnosis

The first step for diagnosing short QT syndrome is ruling out secondary causes, such as the ones cited above. 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.

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 Sudden cardiac arrest = 2 points Polymorphic VT or VF = 2 points Unexplained syncope = 1 point Atrial fibrillation = 1 point

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.
    

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). 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.

SQTS 1,2,3

The QTc is usually < 300-320 msec.

SQTS 4,5,6

The QTc is usually just under 360 msec

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.

Other ECG findings:

• There is a high prevalence of early depolarization patterns on SQTS.
• QRS complex is followed by T wave without any ST segment.

• Prominent U wave separated by isoelectric T-U segment.
• Longer Tpeak - Tend interval.
• Prolongation of the QT interval at slower heart rates is suppressed, remaining below the lower limit.
• Depressed PQ segment commonly observed in the inferior and anterior leads.

• 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.

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). Importantly, lack of inducibility does not exclude a future episode of ventricular fibrillation. 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

• Gene Tests: Short QT Syndrome 1
• Gene Tests: Short QT Syndrome 2
• Gene Tests: Short QT Syndrome 3

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.

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:

• The occurence of tachycardias such as sinus tachycardia and atrial fibrillation.
• Oversensing of the tall, narrow peaked T wave.

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 . Flecainide has not been shown to consistently reduce the inducibility of ventricular fibrillation. Although it does not prolong the QT interval in SQT1 patients, propafenone reduces the risk of recurrent atrial fibrillation in SQT1 patients.

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 I_K 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.

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:

• 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.