Today we discussed an interesting case of a 21 year old male with a non-healing ulcer on his shin. Interestingly he had been recently diagnosed with ulcerative colitis. While, the diagnosis of pyoderma gangrenosum seemed most obvious, the biopsy in fact showed evidence of leukocytoclastic vasculitis and the patient was found to have high peripheral eosinophils and was P-ANCA positive. Talk about a curve ball!

Here are some interesting questions that arose from our discussion:

1) Differential Diagnosis of ulcerative lesion:
Refer to the following NEJM article for an interesting discussion of skin ulcers misdiagnosed as pyoderma gangrenosum. This article gives a great differential diagnosis for ulcerative skin lesions. The key is to have a broad differential and to do a biopsy! The treatment for pyoderma gangrenosum is not benign (steroids and other immunosuppressants) so be sure of the diagnosis before you treat.

2) Leukocytoclastic vasculitis is not a diagnosis in and of itself but a pathologic term describing neutrophilic small vessel vasculitis. It is an indication of small-vessel vasculitis. This can occur in the following settings:

• ANCA associated small vessel vasculitis:  
• Granulomatosis with polyangiitis (formerly known as Wegener's vasculitis)
• Churg-Strauss vasculitis
• Microscopic Polyangiitis
• Immune Complex associated small vessel vasculitis:
• Hepatitis C with cryoglobulinemia
• Henoch-Schonlein pupura (HSP)
• Connective tissue disease-associated vasculitis:
• RA
• SLE
• Sjogren's Syndrome
• Endocarditis
• Hypersensitivy vasculitis:
• Penicillin, ASA, amphetamines, thiazides
• Viral infections:
• Strep throat
• bacterial endocarditis
• TB
• hepatitis
• Staphylococcal infections
• Foreign proteins (serum sickness)

3) Differential for non-vasculitic P-ANCA positivity:

• Infectious: HIV, mycobacterial infections, severe pneumonia, bacterial endocarditis
• Chronic: Rheumaotid arthritis, IBD, Sweet's syndrome, eosinophilia-myalgia syndrome, Goodpasture's syndrome
• Neoplasms: Atrial myxoma, small cell lung cancer, NHL, myelodysplasia, colon carcinoma

See ANCA in diseases other than systemic vasculitis

4) Differential for Eosinophillia:

• Infectious: Parasitic infection, fungal infection (aspergillosis)
• Hematologic/neoplastic: Hypereosinophilic syndromes, leukemia, lymphoma
• Allergic disorders: atopic dermatitis, asthma, rhinitis, medications
• Rheumatic disease: Churg Strauss
• Miscellaneous: Adrenal insufficiency, cholesterol embolization

This morning we discussed an interesting case of an 84 year old male who presented with falls and change in mental status. Dr Nadjafi took us through an approach to delirium (see blog from July 5th for approach to delirium). After thorough investigations it was discovered that the patient's Calcium was 3.98mmol/L! Here is a quick approach to hypercalcemia:

1) Diagnosis:
- Serum Calcium: 40-50% of calcium in serum is bound to protein (mainly albumin). It is the ionized (or "free") calcium that is physiologically important. Therefore, hypo- or hyper-albuminemia can affect the serum ionized calcium. The following calculation helps you determine ionized calcium from measured calcium.

Ionized Calcium = measured Ca + 0.2(40-measured albumin)

- Degree of hypercalcemia: Mild hypercalcemia (<2.75mmol/L) usually seen in hyperparathyroidism. Severe hypercalcemia (>3.25mmol/L) usually indicates malignancy associated hypercalcemia.

2) Symptoms:
 

Neuropsychiatric	Anxiety, depression, cognitive dysfunction In severe cases lethargy and confusion
Gastrointestinal	Abdominal pain, nausea, anorexia and constipation
Renal	- Diabetes insipidis: Inability to concentrate urine, polyuria/polydipsia - Nephrolithiasis: RTA type I: Rare - Nephrocalcinosis from long standing hyperCa: Necrosis of tubular cells and interstitial fibrosis
MSK	- Bony pain (from primary cause ie. Cancer or hyperparathyroidism

"Moans, groans, stones, and psychic overtones"

3) Etiology:

a) PTH Mediated:

• Primary: Sporadic
• Secondary: Renal disease and decreased production of 1,25-dihydroxyvitamin D. Adynamic bone disease results in reduced bone turnover. The reduced uptake of calcium into bones after a calcium load leads to hypercalcemia.
• Tertiary: Prolonged hyperphosphatemia and hypocalcemia leads to hypertrophy of the parathyroid glands and unregulated release of PTH. Occurs in patients post renal transplant.
• Familial: MENI and IIa, familial hypercalciuric hypercalcemia

b) Non-PTH mediated

• Malignancy:
• Osteolytic: Bone mets resulting in induction of local osteolysis by tumor cells and release of osteoclast activating factors in multiple myeloma
• PTHrp: some tumors produce PTH related peptide that mimics PTH. These include squamous cell carcinomas (lung and H+N), breast, bladder, ovarian
• Ectopic PTH secreting tumor
• Granulomatous disease
•  Activation of extra-renal 1-aOH leading in macrophages and/or lymphocytes. Leading to PTH-independent production of 1,25-dihydroxy Vitamin D
• Drugs:
• Lithium
• Thiazides
• Increased Vitamin D intake
• Miscellaneous:
• Immobility
• Hyperthyroidism
• Pheochromocytoma
• Adrenal insufficiency
• Milk alkali syndrome: excessive ingestion of Calcium supplements
• Paget's disease

4) Treatment:

• The cornerstone of treatment is: FLUIDS, FLUIDS, FLUIDS
• Patients are often quitet hypovolemic secondary to their inability to concentrate urine and nephrogenic diabetes insipidus
• The kidneys should be able to excrete the majority of excess calcium
• Also consider:
• Calcitonin: 4u/kg IM/SC rapid reduction in serum Ca by 1-2mmol/L. Works in 4-6 hrs.
• Bisphosphonates: Pamidronate 30mg, 60mg, 90mg IV. More sustained reduction in Ca, takes 1-2 days to start working.
• Steroids: Prednisone 20-40mg/day. Decreases conversion of 25 hydroxyvitamin D to 1,25-dihydroxyvitamin D
• Lasix: Caution as this can cause worsening hypercalcemia. Only used of pt is showing signs of volume overload from fluid resuscitation. see article from Annals of Internal Medicine: Furosemide fro Hypercalcemia: An unproven yet common practice

On Friday we spoke about a case of fever of unknown origin or FUO.
The original definition of FUO as proposed by Petersdorf and Beeson in 1961 required the following criteria:
(1) Fever of >38.3 on more than one occasion
(2) Fever for more than or equal to 3 weeks
(3) No etiology discovered after at least 1 week of inpatient investigations

However, the definition has evolved with the increasing population of patients with HIV and neutropenia and the ability to perform investigations in an outpatient setting. The following is a new definition proposed in 1991 by Durack and Street:

Hayakawa et al. Am J Med Sci. April 3. 2012 Epub ahead of date

A thorough history, including onset, duration and nature of the fever, is crucial. While the pattern of fever has not been found to correlate significantly to the etiology, two patterns have been described: (1)Pel-Ebstein (fever for 3-10 days on, then 3-10 days off, typical of Hodgkin's lymphoma) (2) Typhus inversus: reversal of normal diurnal pattern seen in TB.

In many cases the etiology can be narrowed down based on the patient's social history. Including the patient's country of origin, vaccination status, recent travel history (where exactly), animal or insect exposure, recreational activities (gardening or swimming in fresh water), sexual activity, use of recreational drugs. The most at risk population for acquiring an travel related infectious disease, are those who immigrated long ago and return to their country of origin to "visit friends and relatives" (VFR), as these people tend to be the population who take the least precautions.

The following is a table of common causes of FUO:

Hayakawa et al. Am J Med Sci. April 3. 2012 Epub ahead of date

For a comprehensive approach to FUO refer to the following interesting articles:
http://archinte.jamanetwork.com/article.aspx?articleid=215227

This morning we discussed a case of a 60 year old male with end stage liver disease secondary to Hepatitis C who presented with confusion. Dr Panisko guided us through the process of building a differential diagnosis using the patient's past medical history as a starting point. This is a useful method of organizing your approach, especially when faced with a non-specific presentation such as confusion. Another useful acronym for an approach to delirium is DIMS:

D - Drugs, drugs, drugs
I - Infection
M - Metabolic derangement (endocrine, electrolyte)
S - Structural (intra-cranial process, liver/renal/heart failure)

 Inouye SK. Delirium in older persons. N Engl J Med. 2006;354: 1157-1165

Our patient had multiple possible causes for his confusion:

1) Drugs: Drugs are the most common causes of delirium. Common culprits are psychotropic meds (anxiolytics, antipsychotics, dopamine agonists), anticholinergics, analgesics (opioids), corticosteroids, anticonvulsants etc. Our patient was on seroquel, paroxetine and bupropion, all of which may have contributed to his delirium. One must think of serotonin syndrom given this patient's use of an SSRI. The patient however did not fulfill the Hunter criteria for serotonin syndrome, which includes history of ingesting a seritonergic agent and one of:

• Spontaneous clonus
• Inducible clonus PLUS agitation or diaphoresis
• Ocular clonus PLUS agitation or diaphoresis
• Tremor PLUS hyperreflexia
• Hypertonia PLUS temperature above 38ºC PLUS ocular clonus or inducible clonus

2) Hepatic encephalopathy: Our patient had allegedly stopped his lactulose which puts him at risk for developing hepatic encephalopathy. The pathophysiology of this involves increased blood to brain transport of neurotoxins (such as amonia, amino acids) and biochemical alterations in the uptake and function of neurotransmitters. Up to Date has a good review on the pathophysiology of HE.

3) Infection: Patients with cirrhosis have altered immune defenses and are considered immunocompromised individuals. Changes in gut motility and increased translocation of bacteria can result in increased risk of developing SBP and other infections. Early treatment of infection is important in end stage liver disease (Management of bacterial infections in cirrhosis, J Hepatol. 2012;56 Suppl 1:S1-12)

4) Hyponatremia: Patients with cirrhosis are at risk for developing hyponatremia. This is largely secondary to the systemic vasodilation resulting in the activation of the renin-angiotensin system and ADH, thereby decreaseing the kidney's ability to excrete free water. Treatment for hyponatremia in cirrhosis involves fluid restriction and vasopressin receptor antagonists.

Physical Exam




We reviewed the physical exam for ascites. The following is a table from the JAMA Rational Clinical Exam series for ascites:

JAMA. 1992. 267 (19): 2645-2649

Bottom line:
1. Sensitive tests for Ruling OUT ascites:

• Negative history for ankle swelling/increased abdo girth

• Lack of bulging flanks, flank dullness or shifting dullness

2. Specific tests for Ruling IN ascites:

• Positive shifting dullness and fluid wave

Thiamine Deficiency

 This morning we discussed a case of thiamine deficiency. Thiamine, or Vitamin B1, is a water soluble vitamin, found largely yeast, legumes, pork, rice, and cereals.

Two major thiamine deficiency disorders have been described in adults.

1. Beriberi: hallmark of adult beriberi is symmetrical peripheral neuropathy. Wet beriberi also involved cardiomyopathy and CHF.
2. Wernicke-Korsakoff syndrome: Wernicke is an acute presentation of nystagmus, opthamoplegia, ataxia and confusion. Korsakoff syndrome is the chronic condition that involves impaired short-term memory and confabulation with otherwise grossly normal cognition.

 Uptodate have a good review article on Water soluble vitamin deficiencies.

I like to point you toward a really good review about determinant of healthy eating among low-income Canadians. As we care for our patients, it is very important that we appreciate the socio-economic context of their illness.

Diabetic Foot Ulcers

We discussed diabetic foot ulcers this morning. The best way to prevent these ulcers is early detection of diabetic neuropathy, which is best done with a brief history and screening with Semmes-Weinstein monofilament.

Use the monofilament in 8-10 anatomic sites recommended (see above picture). However, even testing 4 plantar sites on the forefoot identifies 90% of the patients with an insensate site. Monofilament testing is fairly sensitive (66-91% ) and has a very good NPV 94-95%.

Here is review article on preventing diabetic foot ulcers. 

Extended Light's Criteria

This morning we discussed an approach to pleural effusion.

 

One concept we discussed was the possibility of transforming transudative pleural fluid in patients receiving diuretic therapy to an exudate.

In such cases we can use the “extended Light’s criteria”, which is to calculate the total protein gradient (serum minus pleural fluid). The fluid is a transudate if the total protein gradient is greater than 31g/L.

Here is a previous post about the Light’s criteria with a review article by Dr. Light himself!

Bacterial Meningitis

This morning we talked about a case of bacterial meningitis.  This is a disease that is rare but has significant mortality and morbidity, so it is important to be familiar with how to diagnose and treat it. Here are a few key point we discussed this morning.

1. Do not delay antibiotics for procedures such as CT head or LP
2. Antibiotic doses of meningitis are different (and much higher) 
3. Even if the CSFcultures are sterilized by prior antibiotics, other clues such as degree of neutrophillia, CSF glucose level, or the gram stain can point toward bacterial meningitis
4. No everyone needs a CT head
5. IDSA recommendation for CT prior to lumbar puncture is below:
1. Immunocompromised state
2. History of CNS disease Mass lesion, stroke, or focal infection
3. New onset seizure Within 1 week of presentation;
4. Papilledema
5. Abnormal level of consciousness …
6. Focal neurologic deficit
7. fields, gaze palsy, arm or leg drift

 Here is a review from Lance on management of bacterial meningitis. 

**Gram stain CSF: GPC in pairs and short chains suggestive of Streptococcus pneumoniae

KEEP COOL

Given the extreme heat in Toronto recently, I want to bring your attention to a post I did about a year ago about heat stroke, when we were hit with a heat wave and increased admissions. This extreme weather causes no only heat stokes, but also exacerbations of many chronic cardiopulmonary disease.

ABCDE rule

Early recognition of melanoma is an important prognostic factor. To distinguish early melanoma from other forms of benign pigmented lesions, we can use the ABCDE rule.

• Asymmetry (if a lesion is bisected, one half is not identical to the other half)
• Border irregularities
• Color variegation (brown, red, black or blue/gray, and white)
• Diameter ≥6 mm
• Evolving: a lesion that is changing in size, shape, or color, or a new lesion

The diagnostic accuracy of the ABCD vary in different studies. In a retrospective study of 1140 lesions including 460 melanomas, the sensitivity in identifying a lesion as a melanoma was 97 percent when using a single criterion and 43 percent when using all five criteria jointly. By contrast, specificity was 36 percent for a single criterion and 100 percent for all five criteria.

CAM

This morning we discussed a case of delirium.  Although a common diagnosis, it is sometimes challenging to diagnose delirium, especially in patients with underlying dementia or depression. The Confusion Assessment Method (CAM) is a validated tool to help you identify delirium. 

The diagnosis of delirium by CAM requires the presence of features 1 AND 2 plus either 3 OR 4.

1. Acute onset and fluctuating course

2. Inattention

3. Disorganized thinking

4. Altered level of consciousness 

For admitted medical and surgical patients, the CAM has a sensitivity of 94-100% and a specificity of 90-95% for diagnosing delirium.

Here is a detailed explanation of Confusion Assessment Method (CAM).

RS3PE SYNDROME

RS3PE syndrome stands for remitting seronegative symmetrical synovitis with pitting edema.

This syndrome has many similar features to PMR. Patienst are often over the age of 50 and are seronegative. However, unlike PMR, many patients with RS3PE have sudden onset of polyarthritis, usually more prominent distally.

Patients with this disorder respond to low-dose glucocorticoids.

RS3PE also has been described as a paraneoplastic disorder that is associated with solid tumors and hematologic disorders.

Here is a good review article on PMR.

* Areas of pain in PMR

Doctor, my legs are so puffy!

This morning we discussed a case of new onset bilateral leg edema. 

Approach to is to think about one or more of the following etiologies: 1. increased capillary hydrostatic pressure (e.g. CHF) 2. decreased capillary oncotic pressure (e.g. nephrotic syndrome) 3. increased capillary permeability (e.g. inflammation)

As we discussed, focus your history on cardiac, hepatic, or renal disease, or drugs that affect any of those systems.

 Physical examination should focus on the pattern of edema. Is the JVP elevated? Is there pulmonary edema? Is there ascites? Is the edema localized or generalized? Is it pitting or non-pitting? Is it acute or chronic? Pattern of edema will help you narrow down your differential diagnosis.

  Here is a reference on the topic.

Romberg Test

This morning we talked about the Romberg test.

The ability to maintain a steady posture depends on input from 2 of the 3:
o vestibular apparatus
o eyes
o propioception from feet
The cerebellum coordinates the input from all three.

ROMBERG test tells you about problems in propioception or the vestibular apparatus.
The test start with the patient standing with heels together and eyes OPEN. If there is unsteadiness, then there is cerebellar ataxia. If the patient is steady, then ask the patient to stand with eyes CLOSED. Inability to stand for 60 seconds with eyes CLOSED is a positive Romberg sign, and reflects vestibular disease or sensory ataxia.

*The test was named after the German neurologist Moritz Romberg (1795-1873).

Ref: Evidence-Based Physical Diagnosis, McGee. 2007.

"what about my water pill, doctor?"

This morning we briefly talked about the mechanism of action of furosemide (lasix). This drug is a loop diuretics that inhibits the Na-K-2Cl channel in the thick ascending limb of the loop of Henle on the luminal side.

The efficacy of Furosemide is dose-dependent, but a plateau is reached in which even higher doses produce no further diuresis (when all the channels are saturated). The bioavailability of furosemide is only about 50%, so IV is twice as potent as oral. The drug is renally cleared.

IV therapy is preferred in patients with decompensated heart failure initially because drug absorption may be slowed by decreased intestinal perfusion and mucosal edema.

Furosemide is a sulfonamide drug so can cause hypersensitivity reactions, but patients with a history of allergy to sulfonamide antibiotics usually tolerate furosemide with little cross-reactivity.

Another side effect furosemide to be aware of is ototoxicity.

Here is a review article on diuretic therapy.

Pleural Effusion and Ultrasound

At Gel Rounds today, we discussed pleural effusion. The image above is the ultrasound image of a small right sided effusion. The top of the image represents the probe resting on the chest wall, the dark area (e) is the effusion. The Bright band between (e) and the liver is the diaphragm (d). The lung is seen superior and deep to the effusion.

Now that you know how to identify pleural effusion with the ultrasound, use it in addition to your physical exam when doing a bedside thoracentesis.

Prothrombin-Complex Concentrates (PCC )

This morning we discussed the use of PCCs in reversing the INR. PCC is the combinations of vitamin K-dependent coagulation factors (ie, factors II, VII, IX, and X). It is used to normalize the INR and acts more rapidly than FFP or vitamin K alone.

PCC available in Canada is Octaplex (there are more in the market). This is a human blood product derivative (not a recombinant).

Advantage of using PCC is the much lower volume load compared to FFP. Thrombotic complications (such as DIC or MI) have been reported with PCC, but this risk is difficult to quantify.

Vitamin K should be given if you need to completely reveres INR even when using PCC to avoid delayed secondary rise in the INR as the coagulation factors are metabolized (remember factor VII has a half-life of four to six hours in vivo).

The cost of INR reversal with PCC is between $1000-$3000 USD.

Here is a review on reversal of vitamin K agonist therapy.

The Perfect Storm

This morning we discussed a case of thyroid storm. This is a life-threatening condition, characterized by exaggerated symptoms of hyperthyroidism.

Thyroid storm can present as first time presentation of thyroid disease, but more commonly seen in those with long standing history of hyperthyroidism triggered by infection, trauma, surgery, post-partum, or an iodine load.

Patients are often tachycardic with hemodynamic instability, and can have hyperpyrexia, altered LOC, and GI symptoms. Given the high mortality associated with thyroid storm (20-30%), a high index of suspicion should be kept in patients with history of thyroid disease.

Here is a review on thyroid emergencies.

Happy Holidays

On Monday in dermatology morning report we discussed SJS/TEN.

Here is a great reference that our presenter, Dr. A.D., has recommended.

Happy Holidays everyone and see you in January!

Drug-induced liver injury (DILI)

This morning we discussed drug-induced liver injury (DILI). Many drugs, both prescription and over-the-counter, can cause hepatotoxicity, so a careful medication history should always be obtained when a patient presents with liver enzyme abnormalities.

DILI can range from asymptomatic mild enzyme elevations to fulminate liver failure. Jaundice in addition to elevated enzymes is associated with a worse prognosis than that seen in the setting of isolated ezyme abnormalities (an observation known as "Hy's law").

The most important treatment for DILI is cessation of the offending drug.

Here is a review on DILI.

* H& E stain, liver biopsy, atorvastatin-induced acute hepatitis, Inflammatory cell infilteration of the liver parenchyma consistant with inflammation.

Hypersensitivity Pneumonitis

This morning we talked about hypersensitivity pneumonitis- also referred to as extrinsic allergic alveolitis.

This condition is an immunologic reaction of lung parenchyma to an inhaled agent, particularly an organic antigen. HP has been identified in various groups including farmers, bird handlers, carpenters, and those exposed to various industrial dusts. Mold exposure in poor housing can cause HP.

HP can present acutely with abrupt onset of fever, cough, dyspnea, and diffuse fine crackles. CXR may be normal or show transient patchy opacities. Subacute HP presents with gradual development of productive cough, dyspnea, fatigue, anorexia, and weight loss. Respiratory symptoms are more severe than with acute HP, and radiographic findings more extensive.

Removal from exposure to the inciting antigen leads to improvement in symptoms.

* Many adults and children suffer from chronic cough and respiratory symptoms secondary to mold exposure in poor housing in the Northern Ontario Cree community of Attawapiskat.

Here is the CBC photo gallery of the Attawapiskat Housing Crisit.

"once a chief, always a chief...."

This morning, we reviewed a case of HTLV-1 associated T-Cell lymphoma. The human T-lymphotropic virus (HTLV-I) is a retrovirus.

As we discussed, HTLV-1 is also associated with myelopathy, AKA tropical spastic paraparesis (TSP) which causes progressive weakness and spasticity of one or both legs with hyperreflexia.

HTLV-I is diagnosed by serum serology.

Treatment is not indicated for asymptomatic HTLV-1 infection.

*The title of this post has nothing to do with HTLV-1. I just liked Dr. HPK's quote from this morning!

Alcoholic hepatitis

This morning we reviewed a case of Alcoholic hepatitis at morning report.

Updated Post written by Dr. Wong

Alcoholic hepatitis takes place DURING significant alcohol use. They rarely seek medical attention because the hepatitis is mild and resolves on stopping alcohol for a few days. When they do present to ER, it is usually because symptoms persist despite abstinence. Patients rarely recognize jaundice, but in retrospect will have noticed dark urine.

Alcoholic liver disease can be recognized by the findings of AST > ALT, high GGT and high MCV.

Alcoholic hepatitis presents with AST 80-300 > ALT, low grade fever, a rise in WBC/left shift from baseline (baseline may be low), RUQ tenderness. Mild cases (normal INR) have an excellent survival prognosis. Severe hepatitis (INR > 1.9, Bilirubin > 100 or MELD > 21) has a high mortality risk and steroid therapy should be considered.

Therapy is Prednisone 40 mg OD x 4 weeks, no taper. Therapy is contra-indicated in the setting of infection, GI bleeding or renal failure.

Reassess after 1 week, stop if no improvement in bilirubin.

Nutrition with adequate calories is the other mainstay of therapy.

* Coloured light micrograph of a section through the liver of a patient with alcoholic hepatitis, inflammation of the liver due to heavy alcohol consumption. The normally regular cellular structure of the liver has been disrupted here, and large vacuoles of fat (yellow) are seen. The circular structures at centre are bile ducts.

Hypomagnesemia

This morning we reviewed a case of severe hypomagnesemia .

Patients often present with generalized weakness and non-specific complaints, but VENTRICULAR ARRYTHMIA and neurologic finings such as delirium and coma can also occur.

ETIOLOGY
- GI losses: diarrhea
- Renal losses: renal failure or renal magnesium wasting due to drugs such as diuretics, aminoglycosides, or cisplatin, or rare genetic causes such as Gitleman's disease
- Alcohol: causes renal tubular dysfunction and urinary loss of Mg.
- Decrease PO intake

**Think of Magnesium depletion in refractory hypokalemia or unexplained hypocalcemia.

MANAGEMENT:
Route depends on severity and renal function

If hypomagnesemic-hypokalemic ventricular arrhythmias: give 50 meq of IV magnesium slowly over 8 to 24 hours and repeated as necessary to maintain the plasma magnesium concentration above 0.4 mmol/L or 0.8 meq/L.

Oral replacement is adequate for asymptomatic patient.

Treat the underlying disease.

Hypertensive Emergency

We discuss the approach to and management of hypertensive emergency.

Here is a previous post on that topic.