Saturday, December 30, 2023

Ketamine side-effects

Q: Ketamine may cause? (select one)

A) dry-mouth
B) salivation 


Answer: B

Ketamine has become popular in ICUs for sedation and pain management. It is imperative to know its common side effects, one of which is extreme sialorrhea. Non-pharmacologic interventions such as suctioning and proper positioning.

The drug of choice is glycopyrrolate with a single IV dose of 5 mcg/kg IV which can be repeated every two to three minutes with a maximum total dose of 0.8 mg. 

Atropine can also be utilized with a single IV  dose of 0.01 to 0.02 mg/kg IV, with a maximum dose of 1.2 mg. While using Atropine, cardiac effects should be kept in mind.

Ideally, glycopyrrolate or atropine should be kept at the bedside while ketamine is infusing.


#pharmacology



References:

1. Toft P, Rømer UD. Glycopyrrolate compared with atropine in association with ketamine anaesthesia. Acta Anaesthesiol Scand 1987; 31:438.

2. Orhurhu VJ, Vashisht R, Claus LE, Cohen SP. Ketamine Toxicity. 2023 Jan 30. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan–. PMID: 31082131.

3. Schep LJ, Slaughter RJ, Watts M, Mackenzie E, Gee P. The clinical toxicology of ketamine. Clin Toxicol (Phila). 2023 Jun;61(6):415-428. doi: 10.1080/15563650.2023.2212125. Epub 2023 Jun 2. PMID: 37267048.

Friday, December 29, 2023

Phosphate level in acetaminophen-induced acute liver failure

Case: A patient is transferred from a nearby community hospital with acetaminophen-induced acute liver failure. ALT / AST reported in thousands and the last PT-INR of 2.7. On clinical exam, the patient is alert and oriented. Hemodynamics are stable. You alerted the hepatology team and sent STAT labs. After 45 minutes you received a call from the lab with a 'critical value' of phosphate with 0.9 mg/dl. It is a? (select one) (select one)

A) bad sign
B) good sign


Answer: B


Hypophosphatemia in the setting of acetaminophen-induced acute liver failure is a good sign. It indicates the regeneration of hepatocytes and the reversal of acute liver failure. You may have to replace it aggressively. Conversely, hyperphosphatemia suggests impaired regeneration and is a poor prognostic sign. It is also a sign of impending hepato-renal failure due to the kidney's lost ability to lower serum phosphate.

Said that experts warn against relying exclusively on this marker (see reference 3).


#hepatology
#electrolytes


References:

1. Schmidt LE, Dalhoff K. Serum phosphate is an early predictor of outcome in severe acetaminophen-induced hepatotoxicity. Hepatology. 2002 Sep;36(3):659-65. doi: 10.1053/jhep.2002.35069. PMID: 12198658.

2. Yoon E, Babar A, Choudhary M, Kutner M, Pyrsopoulos N. Acetaminophen-Induced Hepatotoxicity: a Comprehensive Update. J Clin Transl Hepatol. 2016 Jun 28;4(2):131-42. doi: 10.14218/JCTH.2015.00052. Epub 2016 Jun 15. PMID: 27350943; PMCID: PMC4913076.

3. Ng KL, Davidson JS, Bathgate AJ. Serum phosphate is not a reliable early predictor of outcome in paracetamol induced hepatotoxicity. Liver Transpl. 2004 Jan;10(1):158-9. doi: 10.1002/lt.20022. Erratum in: Liver Transpl. 2004 Feb;10(2):329. PMID: 14755796.

Thursday, December 28, 2023

PRIS and steroids

Q: The addition of steroids to a patient who is on propofol infusion will  _____________ the risk of propofol infusion syndrome. (select one)

A) decreases
B) increases


Answer: B

Propofol when combined with steroids, acts as a triggering factor for propofol infusion syndrome. 

An improper unsterile handling of propofol may increase the infection rate, though not associated with steroid. Steroid may independently increase the rate of infection.

When continued at rates higher than 5 mg/kg/h for more than 48 hours, propofol may cause rhabdomyolysis, acute renal failure, metabolic acidosis, hyperkalemia, bradycadia, arrhythmia and hyperthermia. Mortality is very high at more than 80%. Syndrome is called 'propofol infusion syndrome' or PRIS. It should be noted that PRIS has been reported even at lower dose or in less than 48 hours time. 

Propofol may turn color of urine green. It is a benign effect of Propofol. Recognition of this side effect is important as it averts unnecessary workup and limits medical expenditures.

#pharmacology


References: 

1. Vasile B, Rasulo F, Candiani A, Latronico N. The pathophysiology of propofol infusion syndrome: a simple name for a complex syndrome. Intensive Care Med. 2003 Sep;29(9):1417-25. doi: 10.1007/s00134-003-1905-x. Epub 2003 Aug 6. PMID: 12904852.

2. Merz TM, Regli B, Rothen HU, Felleiter P. Propofol infusion syndrome--a fatal case at a low infusion rate. Anesth Analg. 2006 Oct;103(4):1050. doi: 10.1213/01.ane.0000239080.82501.c7. PMID: 17000843.

3. Liolios A, Guérit JM, Scholtes JL, Raftopoulos C, Hantson P. Propofol infusion syndrome associated with short-term large-dose infusion during surgical anesthesia in an adult. Anesth Analg. 2005 Jun;100(6):1804-1806. doi: 10.1213/01.ANE.0000153017.93666.BF. PMID: 15920217.

4. Singh A, Anjankar AP. Propofol-Related Infusion Syndrome: A Clinical Review. Cureus. 2022 Oct 17;14(10):e30383. doi: 10.7759/cureus.30383. PMID: 36407194; PMCID: PMC9671386.

Wednesday, December 27, 2023

CXR in PTX

Q: Which phase of respiration on CXR is better to detect pneumothorax (PTX)? (select one)

A) inspiration 
B) expiration 



Answer: B

Inspiration or expiration doesn't affect the volume of air in the pleural space and pneumothorax can be detected better in expiration with less air volume in lung parenchyma, visually magnifying the air in the pleural area.

Said that controversy continues to exist in literature - but the overall literature leans towards doing CXR  in expiration to detect PTX. With the availability of instant digital CXR at the bedside, it may be of value to perform CXR in succession with inspiration followed by  expiration.


#radiology
#pulmonary


References:

1. Thomsen L, Natho O, Feigen U, Schulz U, Kivelitz D. Value of digital radiography in expiration in detection of pneumothorax. Rofo. 2014 Mar;186(3):267-73. doi: 10.1055/s-0033-1350566. Epub 2013 Sep 16. PMID: 24043613.

2. Galanski M, Hartenauer U, Krumme B. Röntgendiagnostik des Pneumothorax auf Intensivstationen [X-Ray diagnosis of pneumothorax in intensive care units (author's transl)]. Radiologe. 1981 Oct;21(10):459-62. German. PMID: 7302201.

3. Cases Susarte I, Sánchez González A, Plasencia Martínez JM. Should we perform an inspiratory or an expiratory chest radiograph for the initial diagnosis of pneumothorax? Radiologia (Engl Ed). 2018 Sep-Oct;60(5):437-440. English, Spanish. doi: 10.1016/j.rx.2017.10.004. Epub 2017 Dec 6. PMID: 29208316

Tuesday, December 26, 2023

LP and CSF draining rate

Q; During lumbar puncture (LP), what is the normal rate of cerebrospinal fluid (CSF) escape via needle into the collecting tube?


Answer; One drop per second

While performing LP, CSF should drop into tube with approximate rate of one drop/sec. A continuous stream of CSF indicates raised intrameningeal pressure.

#procedures


References:

1. Doherty CM, Forbes RB. Diagnostic Lumbar Puncture. Ulster Med J. 2014 May;83(2):93-102. PMID: 25075138; PMCID: PMC4113153.

2. Boyles TH, Gatley E, Wasserman S, Meintjes G. Brief Report: Flow Rate of Cerebrospinal Fluid Through a Spinal Needle Can Accurately Predict Intracranial Pressure in Cryptococcal Meningitis. J Acquir Immune Defic Syndr. 2017 Mar 1;74(3):e64-e66. doi: 10.1097/QAI.0000000000001183. PMID: 28187086.

3. Ellis RW 3rd, Strauss LC, Wiley JM, Killmond TM, Ellis RW Jr. A simple method of estimating cerebrospinal fluid pressure during lumbar puncture. Pediatrics. 1992 May;89(5 Pt 1):895-7. PMID: 1579400.

Monday, December 25, 2023

Merry Christmas




What do you call an intensivist working on Christmas Day? 


 Santa-in-the-box

Sunday, December 24, 2023

Plasma and Serum

Q: What is the difference between plasma and serum?


Answer:

Plasma - is the liquid portion of normal unclotted blood. Plasma consists of 90% water and 10% of elements, antibodies, clotting factors, and other proteins.

Serum - is the clear liquid that can be separated from clotted blood. Serum lacks the formed elements and the clotting factors but retains the electrolytes and soluble proteins, including antibodies. The serum is a Latin word that refers to "whey", the watery liquid that separates from the curds in the process of cheese-making.

#hematology



References:

1. Yu Z, Kastenmüller G, He Y, Belcredi P, Möller G, Prehn C, Mendes J, Wahl S, Roemisch-Margl W, Ceglarek U, Polonikov A, Dahmen N, Prokisch H, Xie L, Li Y, Wichmann HE, Peters A, Kronenberg F, Suhre K, Adamski J, Illig T, Wang-Sattler R. Differences between human plasma and serum metabolite profiles. PLoS One. 2011;6(7):e21230. doi: 10.1371/journal.pone.0021230. Epub 2011 Jul 8. PMID: 21760889; PMCID: PMC3132215.

2. Liu X, Hoene M, Wang X, Yin P, Häring HU, Xu G, Lehmann R. Serum or plasma, what is the difference? Investigations to facilitate the sample material selection decision making process for metabolomics studies and beyond. Anal Chim Acta. 2018 Dec 11;1037:293-300. doi: 10.1016/j.aca.2018.03.009. Epub 2018 Mar 21. PMID: 30292305.

Saturday, December 23, 2023

Transfusion and tetany

Case: 54 years old male with a history of alcoholic cirrhosis was brought to the Emergency Department (ED) after a fall and found to have an intracranial bleed. INR was noted to be 6.5. Neurology service wrote for FFP (fresh frozen plasma) and IV Vitamin K. The Patient was admitted to the ICU after neurosurgery decided to go for non-surgical management. At admission, the patient's mental status seems appropriate, but 4 hours after admission, you have been called as the patient was noted to have seizures by bedside staff. On arrival, you noticed the patient having tetany, but he responded appropriately to your questions. Citrate-induced electrolyte imbalance is suspected. Citrate may cause? (select one)

A) hypocalcemia
B) Hypomagnesemia
C) Both


Answer: C

Citrate is usually used in blood products as an anticoagulant. It binds to free calcium to form soluble calcium citrate, thereby lowering the free (ionized) but not the total serum calcium concentration. It is important to check the ionized calcium instead of total serum calcium. The slower infusion rate has shown significantly less ionized calcium reduction than the higher infusion rates.

Prophylactic calcium infusion is not recommended with each blood product transfusion unless clinically indicated. Citrate is normally rapidly excreted by the liver, and transient hypocalcemia is not necessary to treat. However, when a patient receives more than 1 unit of erythrocytes/blood product every 5 minutes or the capacity of the liver to metabolize citrate effectively is exceeded (like in our patient above with cirrhosis), the associated hypocalcemia can cause depressed ventricular contractility and decreased peripheral vascular resistance, causing arrhythmias, hypotension and neurologic symptoms of tetany.

Moreover, citrate binds to magnesium, which may also result in clinically significant hypomagnesemia.


#electrolytes
#transfusion
#neurology
#hepatology



References: 

1. Hall C, Nagengast AK, Knapp C, Behrens B, Dewey EN, Goodman A, Bommiasamy A, Schreiber M. Massive transfusions and severe hypocalcemia: An opportunity for monitoring and supplementation guidelines. Transfusion. 2021 Jul;61 Suppl 1:S188-S194. doi: 10.1111/trf.16496. PMID: 34269436.

2. Byerly S, Inaba K, Biswas S, Wang E, Wong MD, Shulman I, Benjamin E, Lam L, Demetriades D. Transfusion-Related Hypocalcemia After Trauma. World J Surg. 2020 Nov;44(11):3743-3750. doi: 10.1007/s00268-020-05712-x. Epub 2020 Jul 30. PMID: 32734451; PMCID: PMC7391918.

3. McLellan BA, Reid SR, Lane PL. Massive blood transfusion causing hypomagnesemia. Crit Care Med. 1984 Feb;12(2):146-7. doi: 10.1097/00003246-198402000-00014. PMID: 6697734.

Friday, December 22, 2023

Types of size dependent vasculitis

Q: Behçet syndrome is a? (select one)

A) Large-vessel vasculitis
B) Medium-vessel vasculitis
C) Small-vessel vasculitis
D) Variable-vessel vasculitis 


Answer: D

This question aims to highlight that many vasculitis conditions can't be specified as large, medium, or small. Some vasculitis diseases can involve varying-sized vessels, and no specific-sized arteries are predominantly affected. The prime examples are Behçet syndrome and Cogan syndrome.

A few major vasculitis conditions are mentioned below:

Large-vessel vasculitis 
  • Giant cell arteritis 
  • Takayasu arteritis 
Medium-vessel vasculitis 
  • Polyarteritis nodosa
  • Kawasaki disease
Small-vessel vasculitis 
  • Granulomatosis with polyangiitis and microscopic polyangiitis 
  • Eosinophilic granulomatosis with polyangiitis (Churg-Strauss) 
  • IgA vasculitis (Henoch-Schönlein purpura
  • Cryoglobulinemic vasculitis 
  • Anti-GBM (Goodpasture) disease 
  • Rheumatoid vasculitis 

#Rheumatology


References:

1. Shavit E, Alavi A, Sibbald RG. Vasculitis-What Do We Have to Know? A Review of Literature. Int J Low Extrem Wounds. 2018 Dec;17(4):218-226. doi: 10.1177/1534734618804982. Epub 2018 Dec 3. PMID: 30501545.

2. Younger DS. Overview of the Vasculitides. Neurol Clin. 2019 May;37(2):171-200. doi: 10.1016/j.ncl.2019.01.005. PMID: 30952404.

3. Demir S, Sönmez HE, Özen S. Vasculitis: Decade in Review. Curr Rheumatol Rev. 2019;15(1):14-22. doi: 10.2174/1573397114666180726093731. PMID: 30047330.

Wednesday, December 20, 2023

Organs involvement in SSc

Q: Which of the following organs is relatively more involved in systemic sclerosis (scleroderma / SSc)? (select one)

A) Gastrointestinal  
B) Pulmonary 


Answer: A

Almost 90 percent of patients with SSc have some level of gastrointestinal (GI) involvement, in contrast to pulmonary involvement, which is at about 80 percent. As pulmonary hypertension is one of the dreaded complications of SSc, GI symptoms are usually not as commonly highlighted. Patients with SSc may frequently have dysphagia, choking sensation, heartburn, hoarseness, cough after swallowing, early satiety, bloating, alternating constipation and diarrhea, episodic pseudo-obstruction and bacterial small bowel overgrowth with malabsorption, and fecal incontinence. Other manifestations are vascular ectasia (angiodysplasia) in the antrum of the stomach ("watermelon stomach"), causing unexplained gastrointestinal bleeding and anemia. 

It should be noted that GI symptoms may be contributing to pulmonary symptoms due to long-term microaspiration and the development of Interstitial Lung Disease (ILD).


#rheumatology


References:

1. Nassar M, Ghernautan V, Nso N, Nyabera A, Castillo FC, Tu W, Medina L, Ciobanu C, Alfishawy M, Rizzo V, Eskaros S, Mahdi M, Khalifa M, El-Kassas M. Gastrointestinal involvement in systemic sclerosis: An updated review. Medicine (Baltimore). 2022 Nov 11;101(45):e31780. doi: 10.1097/MD.0000000000031780. PMID: 36397401; PMCID: PMC9666124.

2. Skare T, Culpi M, Yokoo P, Dias M. Gastrointestinal symptoms in scleroderma patients and its influence in body mass index and quality of life. Acta Reumatol Port. 2014 Jul-Sep;39(3):242-7. PMID: 25326404.

3. Marie I, Dominique S, Levesque H, et al. Esophageal involvement and pulmonary manifestations in systemic sclerosis. Arthritis Rheum 2001; 45:346.

Tuesday, December 19, 2023

anti-seizure drug in Torsade de pointes

Q: Which anti-seizure drug can be used to treat Torsade de pointes if conventional therapy fails?


Answer: Phenytoin 

First described in 1969, phenytoin can be utilized when nothing is left to overcome TdeP! It is said to be effective, particularly in arrhythmia, due to digoxin overdose. 

The proposed mechanism is that phenytoin reduces the activity of cardiac ryanodine Receptor 2, which is known for its cardioprotective action.


#cardiology
#pharmacology


References:

1. Yager N, Wang K, Keshwani N, Torosoff M. Phenytoin as an effective treatment for polymorphic ventricular tachycardia due to QT prolongation in a patient with multiple drug intolerances. BMJ Case Rep. 2015 Jun 12;2015:bcr2015209521. doi: 10.1136/bcr-2015-209521. PMID: 26071440; PMCID: PMC4480099.

2. Bhansali S, Tan RBM, Spilios M, Cecchin F. Use of supra-therapeutic phenytoin for management of ventricular arrhythmias in children: Case series and literature review. Pacing Clin Electrophysiol. 2022 Dec;45(12):1385-1389. doi: 10.1111/pace.14565. Epub 2022 Aug 15. PMID: 35903996.

3. Vukmir RB, Stein KL. Torsades de pointes therapy with phenytoin. Ann Emerg Med. 1991 Feb;20(2):198-200. doi: 10.1016/s0196-0644(05)81223-5. PMID: 1996806.

Monday, December 18, 2023

LR vs Saline

Q: Lactate Ringer's contain all of the following EXCEPT? (select one)

A) Sodium
B) Chloride
C) Lactate
D) Potassium
E) Magnesium


Answer: E 

Lactated Ringer's Solution was invented about 150 years ago by a British physiologist, Sydney Ringer, though lactate was added afterward. Normal Saline is the solution of 0.9% NaCl. It has a slightly higher degree of osmolality compared to blood. 

One liter of Normal Saline contains
  • 154 mEq/L of Na+
  • 154 mEq/L of Cl−
One liter of Lactated Ringer's Solution contains:
  • 130 mEq/L of Na+ but total cations of 137 mEq/L , so still is isotonic.
  • 109 mEq/L of Cl−
  • 28 mEq/L of lactate
  • 4 mEq/L of potassium
  • 3 mEq/L of calcium.
Lactate converts to bicarbonate in liver. Patients with lactic acidosis usually have inadequate liver metabolism of lactate, so conversion to HCO3- from the infused lactate of LR is impaired and may give false readings of serial lactate measurements but may be a better choice in regular situations where hyperchloremia restricts the use of normal saline.


#electrolytes
#hemodynamics


References:

1. Maheshwari K, Turan A, Makarova N, Ma C, Esa WAS, Ruetzler K, Barsoum S, Kuhel AG, Ritchey MR, Higuera-Rueda C, Kopyeva T, Stocchi L, Essber H, Cohen B, Suleiman I, Bajracharya GR, Chelnick D, Mascha EJ, Kurz A, Sessler DI. Saline versus Lactated Ringer's Solution: The Saline or Lactated Ringer's (SOLAR) Trial. Anesthesiology. 2020 Apr;132(4):614-624. doi: 10.1097/ALN.0000000000003130. PMID: 31977517.

2. Friederich A, Martin N, Swanson MB, Faine BA, Mohr NM. Normal Saline Solution and Lactated Ringer's Solution Have a Similar Effect on Quality of Recovery: A Randomized Controlled Trial. Ann Emerg Med. 2019 Feb;73(2):160-169. doi: 10.1016/j.annemergmed.2018.07.007. Epub 2018 Aug 23. PMID: 30146446; PMCID: PMC6340785.

Sunday, December 17, 2023

Peres nomogram

Q: What is Peres Nomogram?

Answer: Peres Nomogram is a rule of thumb to ascertain internal jugular central venous catheter's insertion depth based on patient height in centimeters. It was proposed by Dr. Peres from sydney, Australia.

For right internal jugular vein central venous catheters, "height (cm)/10" would provide the appropriate depth of insertion. For example, for a 160-cm tall person, a catheter would be inserted to 16 cm deep but for a 200-cm tall person, the depth would be 20 cm.

For left internal jugular, central venous catheter placements, "height (cm)/10 + 4" would provide the appropriate depth of insertion. For a 160-cm tall person, a catheter would be inserted to 20 cm. For a 200-cm tall person, the depth would be 24 cm. 

It may be of interest to know that external jugulars have been accessed in past for central line with more frequency. In original nomogram external jugulars were mentioned along with internal jugulars.


#procedures


Reference:

Peres PW. Positioning central venous catheters--a prospective survey. Anaesth Intensive Care. 1990 Nov;18(4):536-9. doi: 10.1177/0310057X9001800422. PMID: 2268022.

Saturday, December 16, 2023

Green tea and ALF

Q: 32 years old, a health-conscious female with no past medical history is brought to the emergency department (ED) by family with symptoms of mental status change, nausea, vomiting, and severe jaundice. Patient is reported to be a big fan of herbal and dietary supplements and lately doubled her dose of morning and evening tea.


Answer: Acute Liver Failure (ALF) from Green Tea Extracts

Green tea continues to be popular in all cultures across the globe due to its generalized beneficial effects on the human body and for possible weight loss. The concentrated extract of green tea is called Camellia sinensis L. If consumed in high quantities, it may lead to ALF. Unfortunately, green tea extract is present in many other herbal remedies and a patient may be consuming it without knowledge. Overall these products are known as catechin polyphenols. Women are more prone to hepatic injury than men. Individuals, who practiced prolonged fasting hours along with excess consumption of green tea are more prone to develop ALF.  Fortunately, with discontinuation, ALF is reversible.


# toxicology


References:

1. Gurley BJ, McGill MR, Koturbash I. Hepatotoxicity due to herbal dietary supplements: Past, present and the future. Food Chem Toxicol 2022; 169:113445.

2. Molinari M, Watt KD, Kruszyna T, et al. Acute liver failure induced by green tea extracts: case report and review of the literature. Liver Transpl 2006; 12:1892.

3. Isomura T, Suzuki S, Origasa H, et al. Liver-related safety assessment of green tea extracts in humans: a systematic review of randomized controlled trials. Eur J Clin Nutr 2016; 70:1221.

Friday, December 15, 2023

Euthyroid Sick Syndrome

Q: In Euthyroid Sick Syndrome which of the following eventually rises? (select one)

A) TSH
B) Total T3
C) Total T4
D) Free T4 
E) reverse T3 (rT3) 


Answer: E

Word of wisdom is not to check thyroid function test in ICUs as it takes only a few hours for a patient to ‘abnormalize’ thyroid function test under stress but if clinically indicated, a clinician should send a full "Thyroid Function Test” including TSH, Total T3, Total T4, Free T4, and rT3 (reverse T3). There is no absolute trend but the general rule of thumb is as patients get sicker and sicker 

“all fall but reverse rise” 

 

i.e. rT3 (reverse T3) will be elevated. It is usually at the later stages. 




#endocrinology


References:

1. Lee S, Farwell AP. Euthyroid Sick Syndrome. Compr Physiol. 2016 Mar 15;6(2):1071-80. doi: 10.1002/cphy.c150017. PMID: 27065175.

2. Economidou F, Douka E, Tzanela M, Nanas S, Kotanidou A. Thyroid function during critical illness. Hormones (Athens). 2011 Apr-Jun;10(2):117-24. doi: 10.14310/horm.2002.1301. PMID: 21724536.

3. Krysiak R, Kędzia A, Kowalcze K, Okopień B. [Euthyroid sick syndrome: an important clinical problem]. Wiad Lek. 2017;70(2 pt 2):376-385. Polish. PMID: 29059662.

Thursday, December 14, 2023

CAPS

Q: Catastrophic antiphospholipid syndrome (CAPS) by definition is characterized by severe? (select one)

A) thrombotic complications
B) bleeding complications


Answer: A

Catastrophic antiphospholipid syndrome (CAPS) is an intense life-threatening form of antiphospholipid syndrome (APS) characterized by severe thrombotic complications, microvascular as well as large-vessel thrombosis, over a short period leading to multi-system organ failure (MSOF). There is an interesting discrepancy between the prevalence and presentation. Only 1 percent of patients with APS develop severe CAPS, but almost half of all the patients with APS present with CAPS as their initial manifestations.

Unfortunately, the mechanism of this "thrombotic storm" is still not very well understood. It has been proposed that patients with CAPS may have antiphospholipid antibodies (aPL) with different antigen specificity, avidity, titer, or other features that differ from the aPL in APS causing generalized thrombosis all the body, due to the fact that patients with CAPS have triple aPL positivity with high titer immunoglobulin G (IgG) anticardiolipin and anti-beta2GPI antibodies.

#rheumatology
#hematology



References:

1. Cervera R, Bucciarelli S, Plasín MA, et al. Catastrophic antiphospholipid syndrome (CAPS): descriptive analysis of a series of 280 patients from the "CAPS Registry". J Autoimmun 2009; 32:240.

2. McNeil HP, Simpson RJ, Chesterman CN, Krilis SA. Anti-phospholipid antibodies are directed against a complex antigen that includes a lipid-binding inhibitor of coagulation: beta 2-glycoprotein I (apolipoprotein H). Proc Natl Acad Sci U S A 1990; 87:4120.

3. Ortona E, Capozzi A, Colasanti T, et al. Vimentin/cardiolipin complex as a new antigenic target of the antiphospholipid syndrome. Blood 2010; 116:2960.

4. Kitchens CS, Erkan D, Brandão LR, et al. Thrombotic storm revisited: preliminary diagnostic criteria suggested by the thrombotic storm study group. Am J Med 2011; 124:290.

Tuesday, December 12, 2023

ICP waveform

Q: In intracranial pressure (ICP) waveform, P2 represents intracranial compliance?

A) True
B) False


Answer: A

ICP monitoring waveform has a flow of 3 upstrokes in one wave.

P1 = (percussion wave) represents arterial pulsation
P2 = (Tidal wave) represents intracranial compliance
P3 = (Dicrotic wave) represents aortic valve closure

In normal ICP waveform, P1 should have the highest upstroke, P2 in between, and P3 should show the lowest upstroke (A in the figure below).

If P2 is higher than P1 - it indicates intracranial hypertension (B in the figure below).




#neurology
#trauma
#neurosurgery
#procedures



References:

1. Czosnyka M, Pickard JD. Monitoring and interpretation of intracranial pressure. J Neurol Neurosurg Psychiatry. 2004 Jun;75(6):813-21. doi: 10.1136/jnnp.2003.033126. PMID: 15145991; PMCID: PMC1739058.

2. Kirkness CJ, Mitchell PH, Burr RL, March KS, Newell DW. Intracranial pressure waveform analysis: clinical and research implications. J Neurosci Nurs. 2000 Oct;32(5):271-7. doi: 10.1097/01376517-200010000-00007. PMID: 11089200.

Monday, December 11, 2023

dosing of aminoglycosides

Q: For aminoglycoside dosing, obesity is defined as a Total Body Weight (TBW) greater than what percentage of the Ideal Body Weight (IBW)? (select one)

A) 50%  
B) 100% 
C) 125% 
D) Can't be determined


Answer: C


The first principle of aminoglycoside administration, regardless of the method of administration, is to determine the dosing weight. Patients are usually categorized as underweight, near IBW, and obese.

IBW calculation for males and females differ:
  • IBW, in kg (males) = 50 + (2.3 x inches above 60 inches)
  • IBW, in kg (females) = 45.5 + (2.3 x inches above 60 inches)
For underweight patients, TBW is used.

For patients whose weight is 1 to 1.25 times their IBW, the IBW is used.

For aminoglycoside dosing, obesity is defined as a TBW greater than 125 percent of the IBW, and for such patients, the adjusted body weight (AdjBW) is used with the formula:
  • AdjBW, in kg = IBW + [0.4 x (TBW - IBW)]


#pharmacology


References:

1. Grucz TM, Kruer RM, Bernice F, Lipsett PA, Dorman T, Sugrue D, Jarrell AS. Aminoglycoside Dosing and Volume of Distribution in Critically Ill Surgery Patients. Surg Infect (Larchmt). 2020 Dec;21(10):859-864. doi: 10.1089/sur.2020.012. Epub 2020 Apr 17. PMID: 32302517.

2. Ross AL, Tharp JL, Hobbs GR, McKnight R, Cumpston A. Evaluation of extended interval dosing aminoglycosides in the morbidly obese population. Adv Pharmacol Sci. 2013;2013:194389. doi: 10.1155/2013/194389. Epub 2013 Aug 19. PMID: 24023540; PMCID: PMC3760189.

3. Richard H Drew - Dosing and administration of parenteral aminoglycosides - UptoDate @ https://www.uptodate.com/contents/dosing-and-administration-of-parenteral-aminoglycosides (last accessed November 29, 2023)

Sunday, December 10, 2023

A note on Residual Kidney Function

Over the years, with the increasingly easy access to renal replacement therapies/modalities, the importance of residual kidney function has been less and less appreciated mainly if a patient is not anuric.


It should be remembered that patients who have GFR only at 4 to 5 mL/min are continuously removing large uremic toxins like beta-2 microglobulin, which will not get cleared by dialysis. Similarly, many nonurea solutes, like indoxyl sulfate, and asymmetric dimethylarginine, which are not entirely removed by dialysis, continue to get cleared by residual nephrons even when GFR is less than 1.5 mL/min.

#nephrology


References:

1. Rottembourg J. Residual renal function and recovery of renal function in patients treated by CAPD. Kidney Int Suppl 1993; 40:S106.

2. Toth-Manikowski SM, Sirich TL, Meyer TW, et al. Contribution of 'clinically negligible' residual kidney function to clearance of uremic solutes. Nephrol Dial Transplant 2020; 35:846.

Saturday, December 9, 2023

Gastrointestinal cation exchangers

Q: Which of the following has relatively a quicker action in hyperkalemia to reduce the potassium level? (select one)

A) Patiromer
B) Sodium zirconium cyclosilicate (SZC)


Answer: B

Although hemodialysis (HD) is a recommended treatment for life-threatening hyperkalemic emergency but it may require time to arrange the logistics of HD. Many patients may require insertion of hemodialysis catheter and may not be arranged quickly in many community settings. 

Gastrointestinal cation exchangers such as patiromer, sodium zirconium cyclosilicate (SZC), or sodium polystyrene sulfonate (SPS) are frequently used as an adjuvant treatment along with calcium, sodium bicarbonate and insulin/glucose combo to bridge that time.

SPS is falling out of favor due to its potential side effect of bowel necrosis. SZC is usually preferred over patiromer as it acts relatively faster. SZC (dose of 10 gram) reduces serum potassium by average of 0.37 mEq/L in four hours after the first dose.

#electrolytes


References:

1. Rafique Z, Liu M, Staggers KA, et al. Patiromer for Treatment of Hyperkalemia in the Emergency Department: A Pilot Study. Acad Emerg Med 2020; 27:54.

2. Peacock WF, Rafique Z, Vishnevskiy K, et al. Emergency Potassium Normalization Treatment Including Sodium Zirconium Cyclosilicate: A Phase II, Randomized, Double-blind, Placebo-controlled Study (ENERGIZE). Acad Emerg Med 2020; 27:475.

3. Packham DK, Rasmussen HS, Lavin PT, et al. Sodium zirconium cyclosilicate in hyperkalemia. N Engl J Med 2015; 372:222.

4. McGowan CE, Saha S, Chu G, et al. Intestinal necrosis due to sodium polystyrene sulfonate (Kayexalate) in sorbitol. South Med J 2009; 102:493.

Friday, December 8, 2023

NMB for intubation in organophosphate poisoning

Q: Which of the following neuromuscular blockade (NMB) should NOT be used for intubation in patients with suspected organophosphate (OP) poisoning? (select one)

A) Succinylcholine 
B) Rocuronium


Answer: A

Patients with suspected organophosphate (OP) poisoning should never be intubated with succinylcholine, because it is metabolized by acetylcholinesterase, which is inhibited by OP. This leads to exaggerated and prolonged neuromuscular blockade in these patients. 

Rocuronium which is a non-depolarizing NMB agent is preferred but may require a higher dose as standard doses may be less effective, due to competitive inhibition at the neuromuscular junction. 


#procedures
#toxicology


References:

1. Sungur M, Güven M. Intensive care management of organophosphate insecticide poisoning. Crit Care. 2001 Aug;5(4):211-5. doi: 10.1186/cc1025. Epub 2001 May 31. PMID: 11511334; PMCID: PMC37406.

2. Eddleston M, Mohamed F, Davies JO, Eyer P, Worek F, Sheriff MH, Buckley NA. Respiratory failure in acute organophosphorus pesticide self-poisoning. QJM. 2006 Aug;99(8):513-22. doi: 10.1093/qjmed/hcl065. Epub 2006 Jul 22. PMID: 16861715; PMCID: PMC1525210.

3. Dhanarisi J, Shihana F, Harju K, Mohamed F, Verma V, Shahmy S, Vanninen P, Kostiainen O, Gawarammana I, Eddleston M. A pilot clinical study of the neuromuscular blocker rocuronium to reduce the duration of ventilation after organophosphorus insecticide poisoning. Clin Toxicol (Phila). 2020 Apr;58(4):254-261. doi: 10.1080/15563650.2019.1643467. Epub 2019 Jul 31. PMID: 31364415.

Thursday, December 7, 2023

SCAP score

Q; All of the following are the part of the severe community-acquired pneumonia (SCAP) score EXCEPT? (select one)

A) Systolic blood pressure 
B) Respiratory rate
C) Altered mental status
D) Age 
E) Pulse ox saturation


Answer: E

The severe community-acquired pneumonia (SCAP) is a validated score designed to predict in-hospital mortality, need for mechanical ventilation, and risk for septic shock. It consists of two major criteria and 6 minor criteria.

Major criteria:
  • Arterial pH <7.30 – 13 points
  • Systolic blood pressure <90 mmHg – 11 points
Minor criteria:
  • Respiratory rate >30 breaths/minute – 9 points
  • PaO2/FiO2 <250 mmHg – 6 points
  • Blood urea nitrogen >30 mg/dL (10.7 mmol/L) – 5 points
  • Altered mental status – 5 points
  • Age ≥80 years – 5 points
  • Multilobar/bilateral infiltrates on radiograph – 5 points

A SCAP score ≥10 counting at least one major or at least two minor criteria was found reliable for predicting ICU admission, need for mechanical ventilation, progression to severe sepsis, and treatment failure.

Choice E is wrong as score requires P/F ratio (see above), just not the pulse ox saturation.
  
  
#pulmonary
#scores
  
  
References:
  
1. España PP, Capelastegui A, Gorordo I, et al. Development and validation of a clinical prediction rule for severe community-acquired pneumonia. Am J Respir Crit Care Med 2006; 174:1249.
  
2. Yandiola PPE, Capelastegui A, Quintana J, et al. Prospective comparison of severity scores for predicting clinically relevant outcomes for patients hospitalized with community-acquired pneumonia. Chest 2009; 135:1572.

Wednesday, December 6, 2023

Subcategories of KS

Q: What are the different subcategories of Kaposi sarcoma (KS)?


Answer: Kaposi sarcoma (KS) is an angioproliferative disorder due to human herpesvirus-8 (HHV-8). It is characterized as purplish, reddish blue, or dark brown/black macules, plaques, and nodules on the skin, which may ulcerate and bleed easily. It can be very small to several centimeters in diameter. They can remain unchanged for years or grow rapidly and disseminate. Due to these different characteristics, KS is now subcategorized.

Classic KS - occurs in patients without known HIV and is rarely of clinical significance.

Immunosuppressive treatment–related KS - occurs in patients receiving immunosuppressive therapy for organ transplantation or other indications. This subcategory can be reversible with dosage modification of the immunosuppressive drugs.

African KS - occurs in young males and varies in behavior from indolent to aggressive in the course.

HIV-related KS - occurs in the patient with AIDS.


#oncology


References:

1. Radu O, Pantanowitz L. Kaposi sarcoma. Arch Pathol Lab Med. 2013 Feb;137(2):289-94. doi: 10.5858/arpa.2012-0101-RS. PMID: 23368874.

2. Cesarman E, Damania B, Krown SE, Martin J, Bower M, Whitby D. Kaposi sarcoma. Nat Rev Dis Primers. 2019 Jan 31;5(1):9. doi: 10.1038/s41572-019-0060-9. PMID: 30705286; PMCID: PMC6685213.

Monday, December 4, 2023

Biliary colic

Q: Biliary colic pain is usually? (select one)

A) constant
B) spasmodic


Answer: A

Biliary colic is a misnomer. Biliary pain is usually constant. This misnomer occurs as biliary pain tends to be very intense and provides no relief with movement, squatting, bowel movements, or flatus. Probably due to eventual smooth muscle fatigue or stone passage, the attack typically lasts for about 30 minutes, plateaus at 60 minutes, and slowly subsides within 6 hours. It occurs at the right upper quadrant (RUQ), epigastrium, or sometimes at the substernal area. It may radiate to the back with a tendency towards the right shoulder blade. Associated symptoms are diaphoresis, nausea, and vomiting.

Typically (though not necessary), it is postprandial pain, after a fatty meal.

The acute attack is not associated with fever, tachycardia, lab abnormality, or any peritoneal signs except voluntary guarding. The majority of patients have a recurrence of attack within two years.


#physical-exam
#hepatology


References:

1. Diehl AK, Sugarek NJ, Todd KH. Clinical evaluation for gallstone disease: usefulness of symptoms and signs in diagnosis. Am J Med 1990; 89:29.

2. Festi D, Sottili S, Colecchia A, et al. Clinical manifestations of gallstone disease: evidence from the multicenter Italian study on cholelithiasis (MICOL). Hepatology 1999; 30:839.

3. Thistle JL, Cleary PA, Lachin JM, et al. The natural history of cholelithiasis: the National Cooperative Gallstone Study. Ann Intern Med 1984; 101:171.

Sunday, December 3, 2023

CHS

Q: In cannabis hyperemesis syndrome (CHS) which of the following seems to be most effective? (select one)

A) droperidol
B) ondansetron
C) metoclopramide
D) diphenhydramine 
E) topical capsaicin 


Answer: A

In cannabis hyperemesis syndrome (CHS) it is important to perform detailed history and evaluation. Many institutions/ERs use the Rome IV criteria to diagnose CHS. The most vital strategy is to rule out all other potential causes of hyperemesis.

IV hydration is of paramount importance and works synergistically with antiemetics. 1 L of normal saline or lactated Ringer should be initiated as quickly as possible. Droperidol or haloperidol (dopamine antagonists) are very effective in controlling acute symptoms of CHS.

Ondansetron, metoclopramide, and diphenhydramine are often ineffective in CHS.

Benzodiazepines are partially effective.

Interestingly, topical capsaicin has some weak evidence of effectiveness in CHS.


#toxicology
#GI
#pharmacology


References:

1. Perisetti A, Gajendran M, Dasari CS, et al. Cannabis hyperemesis syndrome: an update on the pathophysiology and management. Ann Gastroenterol 2020; 33:571.

2. ROME Foundation, Rome IV Criteria. https://theromefoundation.org/rome-iv/rome-iv-criteria/ (Accessed on November 24, 2023)

3. Richards JR. Cannabinoid Hyperemesis Syndrome: Pathophysiology and Treatment in the Emergency Department. J Emerg Med 2018; 54:354.

4. Chocron Y, Zuber JP, Vaucher J. Cannabinoid hyperemesis syndrome. BMJ 2019; 366:l4336.

5. Sorensen CJ, DeSanto K, Borgelt L, et al. Cannabinoid Hyperemesis Syndrome: Diagnosis, Pathophysiology, and Treatment-a Systematic Review. J Med Toxicol 2017; 13:71.

Saturday, December 2, 2023

monophasic with biphasic defibrillation

Q: Why biphasic cardioversion is preferred over monophasic cardioversion?


Answer:


In monophasic cardioversion, the current travels only in one direction - from one paddle to the other.


In biphasic cardioversion, the current travels towards the positive paddle, reverses, and returns several times, delivering one cycle every ten milliseconds. They are associated with fewer burns, less myocardial damage, and higher first-shock success.



#hemodynamics
#Code-blue
#resuscitation



References:

1. Higgins SL, Herre JM, Epstein AE, Greer GS, Friedman PL, Gleva ML, Porterfield JG, Chapman FW, Finkel ES, Schmitt PW, Nova RC, Greene HL. A comparison of biphasic and monophasic shocks for external defibrillation. Physio-Control Biphasic Investigators. Prehosp Emerg Care. 2000 Oct-Dec;4(4):305-13. doi: 10.1080/10903120090941001. Erratum in: Prehosp Emerg Care 2001 Jan-Mar;5(1):78. PMID: 11045408.

2. Kudenchuk PJ, Cobb LA, Copass MK, Olsufka M, Maynard C, Nichol G. Transthoracic incremental monophasic versus biphasic defibrillation by emergency responders (TIMBER): a randomized comparison of monophasic with biphasic waveform ascending energy defibrillation for the resuscitation of out-of-hospital cardiac arrest due to ventricular fibrillation. Circulation. 2006 Nov 7;114(19):2010-8. doi: 10.1161/CIRCULATIONAHA.106.636506. Epub 2006 Oct 23. PMID: 17060379.

Friday, December 1, 2023

Symptoms of ACE inhibitor-induced angioedema

Q: Which of the following symptoms is notably absent in Angiotensin-converting enzyme (ACE) inhibitors-induced angioedema? (select one)

A) swelling of the lips, tongue, or face
B) episodic abdominal pain 
C) urticaria and itching 



Answer: C

Although swelling of the lips, tongue, or face is very well known with ACE-inhibitors-induced angioedema, episodic abdominal pain is less well known. Like edema of lips, tongue, or face, intestinal angioedema may also occur leading to episodic abdominal pain.

Urticaria and itching are very unusual.


#allergy-immunology
#pharmacology



References:

1. Kostis WJ, Shetty M, Chowdhury YS, Kostis JB. ACE Inhibitor-Induced Angioedema: a Review. Curr Hypertens Rep. 2018 Jun 8;20(7):55. doi: 10.1007/s11906-018-0859-x. PMID: 29884969.

2. Brown T, Gonzalez J, Monteleone C. Angiotensin-converting enzyme inhibitor-induced angioedema: A review of the literature. J Clin Hypertens (Greenwich). 2017 Dec;19(12):1377-1382. doi: 10.1111/jch.13097. Epub 2017 Oct 10. PMID: 28994183; PMCID: PMC8031276.

Thursday, November 30, 2023

Erythromycin and gastroparesis

Q: Erythromycin improves gastrointestinal motility by mostly acting at? (select one)

A) Gastric fundus
B) Duodenum
C) Jejunum
D) Descending colon



Answer: A

Although not as popular as previously, many clinicians continue to utilize Erythromycin for gastroparesis in inpatient settings. Erythromycin is a motilin agonist and induces high-amplitude gastric propulsive contractions. Erythromycin usually stimulates fundic contractility that inhibits the accommodation response of the proximal stomach after food ingestion. 

Gastroparesis effect can be evident even at very small doses at 40 mg. Erythromycin should not be used more than 250 mg three times daily due to potential side effects. Patients who are not on continuous tube feed in the ICU should be given erythromycin before meals. 
Intravenous Erythromycin is said to be more effective than oral administration.

Potential issues with erythromycin are tachyphylaxis, abdominal pain, ototoxicity (long-term use), bacterial resistance, QT prolongation, and sudden death.

Another utility of erythromycin is to accelerate the transpyloric migration of the tip of an enteral feeding tube, a common issue in ICU.


#nutrition
#pharmacology
#GI


References:


1. Keshavarzian A, Isaac RM. Erythromycin accelerates gastric emptying of indigestible solids and transpyloric migration of the tip of an enteral feeding tube in fasting and fed states. Am J Gastroenterol 1993; 88:193.

2. Bruley des Varannes S, Parys V, Ropert A, et al. Erythromycin enhances fasting and postprandial proximal gastric tone in humans. Gastroenterology 1995; 109:32.

3. Maganti K, Onyemere K, Jones MP. Oral erythromycin and symptomatic relief of gastroparesis: a systematic review. Am J Gastroenterol 2003; 98:259.

Wednesday, November 29, 2023

Poncet Disease

Q: Poncet disease by definition is? (select one)

A) an infectious disease
B) an inflammatory disease


Answer: B

Poncet disease is characterized by four conditions 
  • acute
  • symmetric
  • polyarthritic (small and large joints)
  • associated with active TB

Although it is associated with active extrapulmonary, pulmonary, or miliary TB, it is an inflammatory response without any objective evidence of active TB. The probable cause is immune-mediated. HIV is considered to be a risk factor.

It resolves within a few weeks of initiation of anti-TB therapy. Fortunately, it does not leave any residual joint destruction.


#ID
#rheumatology


References:

1. Isaacs AJ, Sturrock RD. Poncet's disease--fact or fiction? A re-appraisal of tuberculous rheumatism. Tubercle 1974; 55:135.
Sood R, Wali JP, Handa R. Poncet's disease in a north Indian hospital. Trop Doct 1999; 29:33.

2. Arora S, Prakash TV, Carey RA, Hansdak SG. Poncet's disease: unusual presentation of a common disease. Lancet 2016; 387:617.

3. Kawsar M, D'Cruz D, Nathan M, Murphy M. Poncet's disease in a patient with AIDS. Rheumatology (Oxford) 2001; 40:346.

4. Kroot EJ, Hazes JM, Colin EM, Dolhain RJ. Poncet's disease: reactive arthritis accompanying tuberculosis. Two case reports and a review of the literature. Rheumatology (Oxford) 2007; 46:484.

Tuesday, November 28, 2023

SGLT2 and DKA Hx

Q:  Sodium-glucose cotransporter 2 (SGLT2) inhibitors should not be used in patients with a prior history of diabetic ketoacidosis (DKA)?

A) True
B) False


Answer: A

The objective of this question is to enhance the wave of "euglycemic DKA" witnessed in ICUs in the last couple of years. SGLT2 inhibitors should be used with great caution in patients with Type 2 diabetes with eGFR <45 mL/min/1.73 m2, and a prior history of  DKA.

As the Sodium-glucose cotransporter 2 inhibitors mechanism of action is via kidney, it may cause some degree of dehydration. It should also be used with caution in patients who are using nonsteroidal anti-inflammatory drugs (NSAIDs), angiotensin-converting enzyme (ACE) inhibitors/angiotensin II receptor blockers (ARBs), and diuretics. The combined therapy may predispose a patient to Acute Kidney Injury (AKI).

Three other major side effects are
  • genitourinary tract bacterial and yeast infections
  • bone loss and fracture
  • lower extremity infection and amputation, particularly in patients with foot ulceration, neuropathy, foot deformity, and vascular disease

#endocrinology
#nephrology
#pharmacology


References:

1. Halimi S, Vergès B. Adverse effects and safety of SGLT-2 inhibitors. Diabetes Metab. 2014 Dec;40(6 Suppl 1):S28-34. doi: 10.1016/S1262-3636(14)72693-X. PMID: 25554069.

2. Singh M, Kumar A. Risks Associated with SGLT2 Inhibitors: An Overview. Curr Drug Saf. 2018;13(2):84-91. doi: 10.2174/1574886313666180226103408. PMID: 29485006.

3. Pittampalli S, Upadyayula S, Mekala HM, Lippmann S. Risks vs Benefits for SGLT2 Inhibitor Medications. Fed Pract. 2018 Jul;35(7):45-48. PMID: 30766374; PMCID: PMC6368009.

Monday, November 27, 2023

clinical subtypes of Multiple Sclerosis (MS)

Q: What are the three clinical subtypes of Multiple Sclerosis (MS) in adult patients?

Answer: MS is largely categorized into three clinical subtypes depending on behavior over the years, such as flares/exacerbations with full or incomplete recovery, fever, time period, progression, disability, plateaus, temporary minor improvements, and/or superimposed acute relapses.

1. Relapsing-remitting multiple sclerosis (RRMS)
2. Secondary progressive multiple sclerosis (SPMS)
3. Primary progressive multiple sclerosis (PPMS)

RRMS is defined as relapses with either full recovery or with sequelae and residual deficit upon recovery. There is no or minimal disease progression during the periods between disease relapses, though individual relapses themselves may occasionally result in severe residual disability.

SPMS evolves from RRMS; hence, the word "secondary" is used, as over time, the disease enters a stage of steady deterioration in function, with or without superimposed attacks. The relapse rate is typically reduced when the secondary progressive stage is reached. This may be a phenomenon of immunosenescence, as relapses and new MS lesions are less common as people age.

PPMS represents approximately 10 percent of MS cases and is characterized by disease progression from onset, although occasional plateaus, temporary minor improvements, and acute relapses may occur.

The treatment plans are differentiated depending on clinical subtypes.

Some authors mention a fourth type, as the name explains: clinically isolated syndrome (CIS)


#neurology


References:

1. Ghasemi N, Razavi S, Nikzad E. Multiple Sclerosis: Pathogenesis, Symptoms, Diagnoses and Cell-Based Therapy. Cell J. 2017 Apr-Jun;19(1):1-10. doi: 10.22074/cellj.2016.4867. Epub 2016 Dec 21. PMID: 28367411; PMCID: PMC5241505.

2. Fujihara K. [Clinical subtypes of multiple sclerosis and the immuno-pathogeneses]. Nihon Rinsho. 2003 Aug;61(8):1293-9. Japanese. PMID: 12962014.