What Is Going On In Migraine?

Despite the high prevalence of migraines, the underlying pathophysiology is poorly understood.

What was thought?
Cerebral and meningeal arteries dilatation. Now largely disproven.

What do we think?
- MRI says episodic cerebral edema with dilatation of intracereberal vessels and less water diffusion that doesn’t respect vascular territories.

- PET says it’s a subcortical disorder affecting modulation of sensory processing.

- Magneto-EncepaloGraphic (MEG) scan suggests failure of inhibitory circuitry in the visual cortex.

- Hormones play a role. Migraines occur just as commonly in males as in pre-pubertal and post-menopausal females but the ratio tilts towards women of reproductive age group by 3:1. About half of the women complain of migraine synchrony with menses.

- 5-HT overload as suggested by its metabolites in the urine. While the exact significance is controversial, the efficacy of Triptans (5-HT 1b/1d agonists) supports its role.

- Trigeminal nerve dysfunction suggested by blockade of trigeminal nerve impulses by Triptans. They also inhibit release of substance P and pro-inflammatory neuropeptides.

This is what we know so far. To thread this string is your responsibility, future Dr. Neurologist. Good luck!



- Ashish Singh

Hierarchy Of Evidence

Evidence-based medicine is the conscientious and judicious use of current, best research evidence to optimise management plans.
Here’s the order of importance.

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That’d be all.

- Ashish Singh

Reference(s):
1. Evidence based medicine: what it is and what it isn't by Sackett et al, 1996.

Pathophysiology: Diabetic Ketoacidosis

Hello guys, here’s a whiteboard summary of how DKA happens.

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- DKA is a medical emergency. It’s a complication of type 1 diabetes.
- DKA has a triad of hyperglycemia, ketosis [metabolic acidosis] and dehydration.
- Main ketone bodies are beta-hydroxybutyrate and acetoacetate. Acetone is only a minor ketoacid.
- Lactic acidosis also contributes to metabolic acidosis.
- More glucose in blood leads to more glucose filtered into urine causing osmotic diuresis.


- Ashish Singh 

WhiteBoard Summary: Lichen Planus

Hi guys, let’s talk dermatology.

Lichen Planus is a papulosquamous disease that affects skin, nails and mucous membrane, caused by cell-mediated immunity of unknown aetiology. Here’s a (not-so-white) whiteboard summary.

[Please click on the image to enhance it]

- Morphological variants can be hypertrophic, atrophic, erosive, follicular, annular, vesicular, bullous, actinic or pemphigoid.

- Lichenoid reaction can be caused by drugs (thiazides, antimalarials, penicillamine, gold) and even in Graft vs. Host disease.

- Those with steroid resistance/ intolerance are treated by hydroxyquine, methotrexate or sulfasalazine.

- Psoralens can also be used along with UV-A radiation.

- Patient education regarding self-limiting and recurrent nature of the disease is important.

- Ashish Singh

A-a Gradient

A-a gradient =[PAO2 - PaO2]
where:

A-a gradient = difference between alveolar PO2 and arterial PO2

PAO2 = alveolar PO2 (calculated from the alveolar gas equation)

PaO2 = arterial PO2 (measured in arterial blood)

PAO2 =150 - PaCo2/0.8

Normal range for A-a gradient is

10-15 mm Hg

ALL causes of hypoxemia lead to ↑ A-a gradient, EXCEPT:

Hypoventilation, high altitude, upper airway obstruction (e.g. epiglottitis from Haemophilus influenzae, or croup from parainfluenza virus)

Everything else will cause ↑ A-a gradient (e.g. shunt, V/Q mismatch, etc.).  

It's much better to remember the exceptions, then everything else becomes the rule!

Also to adjust for age, the thumb rule to calculate A-a gradient is :

Age /4   plus 4

A-a gradient >30 is considered elevated regardless of age.

Bhopalwala. H

Lung Biopsy in VAP

Lung biopsy in Ventilator-associated Pneumonia may be reserved for patients in whom infiltrates are progressive despite antibiotic therapy or patients in whom a non-infectious etiology is suspected.

The purpose of acquiring tissue under these circumstances is to identify a pathogen that may have been missed with previous sampling or a pathogen that is difficult to culture (eg, fungus, herpes viruses) or to identify a noninfectious process masquerading as infection (eg, cancer, cryptogenic organizing pneumonitis, lymphangitis, interstitial pneumonitis, vasculitis).

Source: Uptodate

Bhopalwala. H

Catheter Related Candidemia Treatment Indications

Empiric therapy for suspected catheter-related candidemia should be administered for septic patients with the following risk factors:

●Total parenteral nutrition

●Prolonged use of broad-spectrum antibiotics

●Hematologic malignancy

●Hematopoietic cell or solid organ transplant

●Femoral catheterization

●Colonization due to Candida species at multiple sites

Source: Uptodate

Bhopalwala. H

Antibiotic Lock Therapy

Antibiotic lock therapy —

The premise of ALT is to achieve sufficient therapeutic concentrations to kill microbes growing in a biofilm . ALT may be a useful adjunctive therapy together with systemic antibiotic therapy for intraluminal infections due to coagulase-negative staphylococci or gram-negative organisms in the setting of CRBSI (Catheter Related Blood Stream Infection) when the catheter cannot be removed .

ALT should not be used for extraluminal infections nor for management of infections due to S. aureus, P. aeruginosa, drug-resistant gram-negative bacilli, or Candida.

Source: Uptodate

Bhopalwala. H

Timing of Catheter Replacement in CRBSI

In general, the patient should receive antibiotic therapy for at least two to three days following device removal prior to device replacement. At the time of device replacement, the patient should be hemodynamically stable with negative blood cultures and no sequelae of bloodstream infection .In addition, for patients with CRBSI ( Catheter Related Blood Stream Infection) due to S. aureus, a new catheter may be placed if additional blood cultures demonstrate no growth at 72 hours

Source: Uptodate

Bhopalwala. H

Right to left shunt causing Hypoxemia

A right-to-left shunt exists when blood passes from the right to the left side of the heart without being oxygenated. There are two types of right-to-left shunts:

●Anatomic shunts exist when the alveoli are bypassed. Examples include intracardiac shunts, pulmonary arteriovenous malformations (AVMs), and hepatopulmonary syndrome.

●Physiologic shunts exist when non-ventilated alveoli are perfused. Examples include atelectasis and diseases with alveolar filling (eg, pneumonia, acute respiratory distress syndrome).

Right-to-left shunts cause extreme V/Q mismatch, with a V/Q ratio of zero in some lung regions. The net effect is hypoxemia, which is difficult to correct with supplemental oxygen.

The degree of shunt can be quantified from the shunt equation:

Qs/Qt  =  (CcO2  -  CaO2)  ÷  (CcO2  -  CvO2)

where Qs/Qt is the shunt fraction, CcO2 is the end-capillary oxygen content, CaO2 is the arterial oxygen content, and CvO2 is the mixed venous oxygen content. CaO2 and CvO2 are calculated from arterial and mixed venous blood gas measurements, respectively. CcO2 is estimated from the PAO2.

Source: UpToDate

Bhopalwala. H

Causes of Hypoventilation

Hypoventilation — 

The lung alveolus is a space in which gas makes up 100 percent of the contents. This means that once the partial pressure of one gas rises, the other must decrease. Both arterial (PaCO₂) and alveolar (PACO₂) carbon dioxide tension increase during hypoventilation, which causes the alveolar oxygen tension (PAO₂) to decrease. As a result, diffusion of oxygen from the alveolus to the pulmonary capillary declines with a net effect of hypoxemia and hypercapnia. Because the respiratory quotient (Defined as CO_{2 eliminated}/O_{2 consumed}) is assumed to be 0.8, hypoventilation affects PaCO₂more than O₂.

Hypoxemia due to pure hypoventilation (ie, in the absence of an elevated A-a gradient) can be identified by two characteristics. First, it readily corrects with a small increase in the fraction of inspired oxygen (FiO₂). Second, the paCO₂ is elevated. An exception exists when the hypoventilation is prolonged because atelectasis can occur, which will increase the A-a gradient . Abnormalities that cause pure hypoventilation include:

●CNS depression, such as drug overdose, structural CNS lesions, or ischemic CNS lesions that impact the respiratory center

●Obesity hypoventilation (Pickwickian) syndrome

●Impaired neural conduction, such as amyotrophic lateral sclerosis, Guillain-Barré syndrome, high cervical spine injury, phrenic nerve paralysis, or aminoglycoside blockade

●Muscular weakness, such as myasthenia gravis, idiopathic diaphragmatic paralysis, polymyositis, muscular dystrophy, or severe hypothyroidism

●Poor chest wall elasticity, such as a flail chest or kyphoscoliosis

Bhopalwala. H

Restrictive vs Liberal approach to transfusion in Sepsis

Hello everyone, 

Here are some studies on approach to blood transfusion during sepsis:

One multicenter randomized study of 998 patients with septic shock reported no difference in 28-day mortality between patients who were transfused when the hemoglobin was ≤7 g/dL (restrictive strategy) and patients who were transfused when the hemoglobin was ≤9 g/dL (liberal strategy) . The restrictive strategy resulted in 50 percent fewer red blood cell transfusions (1545 versus 3088 transfusions) and did not have any adverse effect on the rate of ischemic events (7 versus 8 percent).

One randomized trial initially reported a mortality benefit from a protocol that included transfusing patients to a goal hematocrit >30 (hemoglobin level 10 g/dL) . However, similarly designed studies published since then reported no benefit to this strategy. 

Bhopalwala. H

Source: UpToDate 

Vasopressin in ICU

Vasopressin (arginine-vasopressin) Pitressin, Vasostrict

0.03 units per minute (alternatively 0.01 to 0.03 units/minute initially) 0.03 to 0.04 units per minute (not titrated)
0.04 to 0.07 units/minute;

Doses >0.04 units/minute can cause cardiac ischemia and should be reserved for salvage therapy

Add-on to norepinephrine to raise blood pressure to target MAP or decrease norepinephrine requirement. Not recommended as a replacement for a first-line vasopressor.
Pure vasoconstrictor; may decrease stroke volume and cardiac output in myocardial dysfunction or precipitate ischemia in coronary artery disease.

Must be diluted; eg, a usual concentration is 25 units in 250 mL D5W or NS (0.1 units/mL)

Bhopalwala. H

Classification Criteria for Adult Still Disease

●Yamaguchi criteria – The Yamaguchi criteria require the presence of five features, with at least two being major diagnostic criteria . In addition, the presence of any infection, malignancy, or other rheumatic disorder known to mimic ASD in its clinical features precludes the diagnosis of ASD, at least for the purpose of research.

The four major Yamaguchi criteria are:

•Fever of at least 39ºC (102.2ºF) lasting at least one week

•Arthralgias or arthritis lasting two weeks or longer

•A nonpruritic macular or maculopapular skin rash that is salmon-colored in appearance and usually found over the trunk or extremities during febrile episodes

•Leukocytosis (10,000/microL or greater), with at least 80 percent granulocytes

The minor Yamaguchi criteria include:

•Sore throat

•Lymphadenopathy

•Hepatomegaly or splenomegaly

•Abnormal liver function studies, particularly elevations in aspartate and alanine aminotransferase and lactate dehydrogenase concentrations

•Negative tests for antinuclear antibody (ANA) and rheumatoid factor (RF)

Bhopalwala. H

HAP and VAP

Pneumonia types — The 2016 Infectious Diseases Society of America (IDSA)/American Thoracic Society (ATS) guidelines distinguish the following types of pneumonia :

●Hospital-acquired (or nosocomial) pneumonia (HAP) is pneumonia that occurs 48 hours or more after admission and did not appear to be incubating at the time of admission.

●Ventilator-associated pneumonia (VAP) is a type of HAP that develops more than 48 hours after endotracheal intubation.

Bhopalwala. H

qSOFA Score for Sepsis

The qSOFA (quick Sequential Organ Failure Assessment) score is easy to calculate since it only has three components, each of which are readily identifiable at the bedside and are allocated one point:

●Respiratory rate ≥22/minute

●Altered mentation

●Systolic blood pressure ≤100 mmHg

Bhopalwala. H

GPA vs MPA Flares

The distinction between GPA ( Granulomatosis with Polyangiitis) and MPA (Microscopic Polyangiitis) is important chiefly because of differential tendencies to flare. Although both diseases may flare after the achievement of remission, GPA is substantially more likely to relapse.

That's all.

Bhopalwala. H

ANCA titers and Disease flare.

Does a rise in ANCA titers predict a disease flare? — This has been a controversial area in the literature almost since ANCA were first identified in the 1980s. However, several rigorous studies have demonstrated that elevations in the titers of ANCA do not predict disease flares in a timely manner . The largest of these studies was performed on a clinical trial cohort of 180 patients (Wegener's Granulomatosis Etanercept Trial [WGET] Research Group, 2005), with serum samples drawn at three-month intervals and ANCA assays performed at the Mayo Clinic . The following findings were observed:
●Among patients who were PR3-ANCA positive compared with negative at baseline, there were no differences in the median time to relapse, disease activity score , or organ involved at relapse. Decreases in PR3-ANCA levels were not associated with a shorter time to remission, and increases were not associated with relapse.
●Relapses occurred among 46 of 101 patients (46 percent) who were mature-PR3-ANCA positive at baseline and achieved remissions of at least six months' duration. However, the proportion of patients who experienced a disease flare within one year of an elevation in ANCA titer was only 40 percent.
Other studies have come to slightly different conclusions, indicating that persistently high or rising titers of ANCA are associated with an increased risk of disease relapse . However, even in those studies, the temporal relationship between a rise in ANCA titer and the occurrence of a disease flare was poor. As an example, in a prospective study of 100 ANCA-positive patients observed over a two-year period, relapse did not occur in 43 and 29 percent of those with a rise in ANCA titers by immunofluorescence and in PR3-ANCA titers by ELISA, respectively .
In addition, a meta-analysis of 18 studies found that neither a rise in ANCA titer nor a persistently elevated ANCA titer were strong predictors of a subsequent disease flare . Therapies for relapsed ANCA-associated vasculitis (often, high doses of glucocorticoids and cytotoxic agents) carry substantial risk, including severe infections, cystitis, bladder cancer, lung fibrosis (rarely), and death. Treating all patients with increases in ANCA titers would result in unnecessary risks of toxicity in a substantial percentage of patients, nearly 30 percent in the study mentioned above. Because of these concerns, using a rise in ANCA titer as the sole parameter to justify altering immunosuppressive therapy cannot be endorsed.
A reasonable recommendation is to closely follow patients with rising ANCA titers but not to alter their therapy unless there are clear clinical signs of active disease.

Bhopalwala. H

POTS Syndrome

●The postural tachycardia syndrome (POTS) is defined as a form of orthostatic intolerance characterized by an excessive increase in heart rate that occurs on standing without arterial hypotension.

●The etiology of POTS is not clear, but the disorder may be heterogeneous. Abnormalities in autonomic regulation that may either be genetic or acquired are described. Proposed mechanisms include partial sympathetic denervation leading to discordant cardiac and vascular sympathetic control, hypovolemia and impairment of the renin-angiotensin-aldosterone system, venous abnormalities and baroreflex dysfunction.

●The clinical symptoms of POTS are varied and nonspecific, and include dizziness, lightheadedness, weakness, blurred vision, and fatigue upon standing. The orthostatic nature of the symptoms is the primary clue to the diagnosis.

●The diagnosis of POTS is established from the history and head-up tilt testing which demonstrates a heart rate increase of >30 bpm over baseline or to >120 bpm. Dehydration, prolonged bedrest, medications, and other dysautonomias should be excluded as etiologies.

●The optimal therapy of POTS is not established. Patients should avoid precipitating factors, and physical activity should be encouraged. We suggest volume repletion and fludrocortisone (0.05 to 0.2 mg per day) as the first line of therapy . Some patients may benefit from midodrine or beta blocking agents. Other therapies remain under investigation, and further confirmation of benefit is needed before they can be recommended.

Bhopalwala. H

Classification of Cryoglobulinemia

●The Brouet classification criteria is the most commonly used system that classifies cryoglobulinemia into three different subgroups based on their Ig composition. These classification criteria are also useful in that the subgroups partly correlate with pathogenicity and clinical manifestations.

•In type I cryoglobulinemia, the cryoglobulins are monoclonal Ig, typically IgG or IgM, and less commonly IgA or free Ig light chains. Type I cryoglobulinemia develops in the setting of protein-secreting monoclonal gammopathies such as a monoclonal gammopathy of undetermined significance (MGUS) or a B-cell lineage malignancy (eg, multiple myeloma, Waldenström macroglobulinemia, or chronic lymphocytic leukemia).

•In type II cryoglobulinemia, the cryoglobulins are composed of a mixture of a monoclonal IgM (or IgG or IgA) with rheumatoid factor (RF) activity and polyclonal Ig. Type II cryoglobulins are often associated with persistent viral infections, particularly hepatitis C virus (HCV) infection, and are associated with the mixed cryoglobulinemia syndrome. Other clinical associations with type II cryoglobulinemia include other infections such as hepatitis B virus (HBV), HIV, autoimmune diseases (mainly systemic lupus erythematosus [SLE] and Sjögren's syndrome), and lymphoproliferative disorders.

•In type III cryoglobulinemia, the cryoglobulins are composed of a mixture of polyclonal IgG (all isotypes) and polyclonal IgM. These cases are often secondary to autoimmune disorders, but can also be associated with infections (mainly HCV).

Bhopalwala. H