Friday, December 13, 2013

Pulmonary Hypertension 

In morning report today we discussed the case of an elderly patient who presents with dyspnea. Specific points include an echocardiogram that showed a normal LV, with no significant diastolic dysfunction, but reported a very elevated RVSP (over 100). 

Given the absence of obvious left sided heart disease as the cause and suggestions of high right sided pressures, the diagnosis of pulmonary hypertension was raised. 

Approach to pulmonary hypertension

An anatomical approach is useful and from this come the 5 major categories of disease.

1. PAH (pulmonary  artery hypertension)
-idiopathic, hereditary ((bmpr2, alk (alk mutations, not the ones that cause cancer, can lead to PAH, and HHT))
-secondary to CTD (scleroderma more often CREST, anticentromere…whereas anti-scl70 is systemic, causes ILD), HIV, 
-hemoglobinopathies (ie sickle cell, anything with hemolysis leads to binding of NO that prevents vasodilation), drugs (amphetamines, cocaine, fen-phen)

1 prime: PVOD (pulmonary veno-occlusive disease)

PVOD vs PAH: one defining feature is that if PVOD receives PAH treatment, they will get significantly worse.

2. Cardiac: CHF, LV dysfunction, AS, MR, diastolic

3. Lung disease: Chronic hypoxemia eg COPD, OSA, hypoventilation syndrome or parenchymal lung disease eg ILD

4. CTEPH: treated with endarterectomy (surgery)

5. Miscellaneous: sarcoid, langerhan’s, splenectomy, mpd, glycogen storage diseases

History, physical 
-looking for consequences of and causes of pulmonary hypertension:

-Elevated JVP, CV, loud P2, palpable P2, RV heave, SOA, pulsatile liver.

PFT’s (also 6 minute walk test for prognostication, not diagnostic)
- looking for lung disease
- normal pft but isolated dlco would be hint to IPAH

-Normal RVSP is 35
-RV dilatation, RV hypokinesis, pericard effusion

V/Q scan
-looking for CTEPH
-CT is good for acute, but not chronic. If V/Q positive, CT normal, then think of CTEPH

High res CT with contrast
-for parenchymal lung disease. Contrast is to help look for PE’s

Sleep study

-CTD, HIV, Hgb electrophoresis etc.

Right heart catheterization
-mPAP > 25 with PCWP < 15
-Trans pulm grad is mPAP – PCWP  If > 12 then abnormal

Treatment considerations include:
- Oxygen 
- Diuretics 
- Anticoagulation (controversial)

Condition specific treatments include: 
For CTEPH: endarterectomy, Riociguat (recent NEJM link is here)

PAH: endothelin antagonist such as bosentan, vasodilators such as PDE5 inhibitors, IV epoprostenol

Lastly is transplant.

For more check out this BMJ review article on pulmonary hypertension, also where the above figure comes from.

Tuesday, December 10, 2013

A rash diagnosis

Morning report discussed a case of a patient who presented with non specific symptoms such as nausea, vomiting, subjective fevers, and back pain.

Based on this, proposed diagnoses based on symptom/syndrome recognition included pyelonephritis, vertebral osteomyelitis, epidural abscess. 

If the patient was delirious, how would your consideration change?
Perhaps age factors into this and would be appropriate if this were a patient who was elderly with vascular injury in the past. 

Delirium might invoke CNS infections, or may be secondary to the primary process. 

Physical examination revealed a vesicular rash, in a dermatomal distribution. 

These lesions were de-roofed and sent for analysis, which came back as VZV.


Primary infection with VZV = Chicken Pox. Latency develops in dorsal nerve roots.

Reactivation then occurs: 
-Can be with rash = shingles, dermatomal distribution
-Can be without rash = zoster sine herpete
-Reactivation can present with or without visceral involvement eg. pancreatitis, hepatitis

Age is the biggest risk factor on a population basis for reactivation.

Neurologic complications of VZV include:

-         Zoster opthalmicus
-         Bell’s Palsy
-         Ramsay Hunt
-         Immunocompetent: can develop
o       Transverse myelitis
o       Granulomatous angiitis – can present as stroke

-         Immunocompromised:
o       Transverse myelitis
o       Small vessel vasculopathy – present as encephalitis

o       Post herpetic neuralgia defined as pain > 90 days after onset of rash. Age again  is RF.

Zoster associated pain comprises phase of acute neuritis and post herpetic neuralagia

-         Acyclovir, Famcyclovir, Valcyclovir. (FCV,VCV may be considered over ACV because of activity, dosing)
-         Decrease rash by 0.5 day, decrease fever by 0.5 day, decrease acute neuritis phase
-         Treatment should be within 72 hours of rash. Exceptions include zoster opthalmicus, immunocompromised, one could argue for Bell's Palsy.

Post Herpetic Neuralgia treatment
-         gabapentin, TCA’ clear direction over which to choose, which is better. Acetaminophen, NSAIDs may help.

Other points in management include getting an ophtho assessment if V1 is involved. The role of steroids is controversial.

-         Indicated for greater than 60 yo
-         50% reduction in shingles
-         67% reduction in zoster associated pain
-         Similar results greater than 50 yo
-         Cannot give if on immunosupression. Should wait at least 6 months

-         Not clear when to give after acute zoster infection…

For more details see this NEJM review article on Zoster

...and this NEJM article on neurologic complications of Zoster

Wednesday, November 20, 2013

Complications of Alcohol

Today in morning report we discussed a patient presenting with worsening peripheral edema and ascites. 

This patient has a known history of cirrhosis secondary to alcohol.

It is important when assessing patients to have a framework of the likely causes for why they are presenting today, as well as to consider all of the dangerous complications/consequences of their underlying condition that often plays a role in their presentation. This will also help to shape your history/ddx/communications of the case.

In a patient with cirrhosis, some issues to consider when assessing:

1. Encephalopathy, also remember, think about what has caused their encephalopathy
2. SBP (Spontaneous bacterial peritonitis)
3. GI bleeds, specifically variceal bleeds.
4. Hyponatremia and neurologic sequelae from that.

Back to this patient. When assessed, there was no neurologic symptoms, mental status was normal, no evidence of asterixis. There was no abdominal tenderness, no fevers/chills/sweats. Lastly there was no evidence of melena stools or hematemesis. 

Because of his change in clinical status, the question of SBP was raised, and so a diagnostic tap was performed. 

A word on SBP:

Changes in clinical status in a patient with cirrhosis essentially warrants a diagnostic tap to ensure that they have not developed SBP. remember that SBP is mono-microbial due to transient bacteremia returning and seeding the ascitic fluid. It is not as previously thought due to GI translocation (if it were, would see polymicrobial infections). 

When doing your diagnostic tap, keep the number 250 in your head, which is the cut off of neutrophils below which is sensitive to rule out SBP.

If SBP is suspected, empiric treatment is targeted and enteric organisms and is often a 3rd generation cephalosporin. Additionally, for the treatment of SBP we will use albumin (in the absence of any other contraindications). In 1999 a study in the NEJM looked at ~65 patients in each arm of either cefotaxime or cefotaxime + albumin. Rates of renal impairment, and mortality were approximately 30% in the cefotaxime only arm compared to 10% in the cefotaxime + albumin arm. This gives an ARR of 20% and so a NNT of 5!! Granted was a small study, and the patient population needs to be assessed for whether it applies to your patient. However, this is an oft cited trial to support the use of albumin in SBP.

Last word on the neurologic complications of alcohol:

Acutely and most commonly is the intoxicating effects that alcohol has.
More seriously in the acute setting think about alcohol withdrawal, delirium tremens, Wernicke's. Chronically peripheral neuropathy, midline cerebellar disease, and rarely the marchiafava-bignami syndrome which is disease of the corpus callosum. 

See the 1999 NEJM SBP Albumin trial here

Wednesday, November 13, 2013

The definition is in the name.

Morning report discussed a case of a patient who was initially admitted for mild volume overload that was treated appropriately in the standard fashion, but while in hospital, abnormalities were noted on the patient's laboratory investigations...

They included:

1. Rising creatinine
2. Rising phsophate
3. Dropping Calcium
4. Very elevated uric acid

Context helps, and the further information revealed that this patient has a history of a hematologic malignancy, that has been treated with aggressive, multi-modal chemotherapy, and unfortunately has recurred with signficant tumour burden.

Diagnosis......Tumour Lysis Syndrome.

Tumour Lysis Syndrome (TLS) is aptly named, and helps to understand the basic pathophys.

Tumour cells breakdown and release their intracellular contents, specifically K, UA, PO4, and as a result of the high PO4, binds and lowers Ca.

Thus there are laboratory criteria for TLS, essentially being:
1. Hyperkalemia
2. Hyperuricemia
3. Hyperphosphatemia
4. Hypocalcemia.

Clinical criteria, are essentially all the downstream problems that the above can cause, with the big categories being:
1. AKI (think about calcium, UA, possibly xanthine precipitation)
2. Cardiac (dysrhytmias from K and Ca abnormalities)
3. Neuro (tetany, seizures)
TLS also can lead to a general inflammatory "SIRS" like reaction that can contribute to multi-organ failure.

Risk Factors for TLS include
1. Type of cancer (usually hematologic, rapidly progressive, but now noticing in other cancers previously thought to be rare).
2. Tumour burden (ie mets, bulk).
3. Treatment factors: highly aggressive, rapid cell turnover treatment 
4. Patient factors: do they have underlying kidney disease, hypovolemia, etc.?
5. MD factors: did we prophylax, give fluids

Priniciples of management:
1. Fluids, fluids, fluids
2. Excretion: whether through agents such as rasburicase (that facilitate excretion by converting UA to allantoin. Remember that allopurinol only inhibits formation of more UA, but does not mediate excretion.
Diuretics can be used. Dialysis often considered in severe cases. 

See this 2011 review article from the NEJM for more details.

Friday, November 8, 2013

The diagnosis is stroke...

wait how old is the patient?

In morning report we discussed a patient who presented with a history of expressive aphasia and right sided weakness.

If this patient were 80 years old with atrial fibrillation not anticoagulated, or if they had multiple vascular risk factors, then it would be a common case of ischemic stroke that we encounter not infrequently.

How would your diagnostic consideration change if this patient were 20, 30 or 40 years old?

In other words, how do you approach stroke in the young?

Before we explore that, remember to be diligent with your neurologic history to clarify:
1. time course
2. characteristics
3. localization
4. associated symptoms (important, and should revolve around your DDx).

This patient had difficulty speaking, remember that when assessing for a language problem, try to distinguish if there is a deficient in comprehension, repetition, naming, or fluency. Language localizes to the left perisylvian region.

The time course was over a couple days with primarily language deficits and mild weakness (later confirmed on exam). There were no obvious assoicated symptoms that we will explore in detail later.

Physical examination should be meant to help confirm/disconfirm your working diagnosis that was made from your history. Remember that the neurologic exam starts with:

1. Mental status: Language is part of the mental status exam
2. Cranial Nerves
3. Motor: not just power!
4. Reflexes
5. Sensory
6. Coordination

This patient's physical exam confirmed word-finding difficulties and mild right sided weakness with no other abnormalities found on exam.

Imaging revealed a left MCA territory infarct and this patient is currently being managed and worked up to determine the etiology of the stroke.

A word on neuro-imaging (I am not a radiologist by any means, but some useful a sense radiology for dummies 101):

CT findings for stroke include: loss of grey/white matter differentiation, ribboning, sulcal effacement, MCA sign.
When looking at an MRI for stroke, one approach is first look at the FLAIR sequence...a stroke is white. Then look at the DWI (look at the 2nd or 3rd sequence), stroke should still be white...lastly look at the ADC: stroke will be black.

This patient was young, and getting back to the diagnostic approach for "Stroke in the Young".

Remember to consider the causes you normally would and so looking for vascular disease, arrythmia (atrial fibrillation) is still part of the work up.

Other etiologies and clues:

1. Arterial:
- Consider dissection, especially if there is a history of trauma, or neck manipulation, and especially if you detect a Horner's.
- Arterial embolism can result  from hypercoaguable states (thrombophilias, PV, APLA) as well as from emboli from other sources such as endocarditis.
- Consider other arteriopathies such as moya-moya 

2. Venous
- Venous sinus thrombosis can occur, especially in the setting of risk factors such as high estrogen containing OCP, and consider in a young patient with stroke complaining of headache.

3. Cardiac
- as previously mentioned endocarditis (both infectious and non- ie Libman-Sacks endocarditis in SLE)
- Cardiac anomalies, ventricular or atrial thrombi, PFO (controversial)

4. Medications
- In particular think of illicit drug use, such as stimulants that may further put at risk for hypertension, dissection.

5. Thrombophilia
- Includes myeloproliferative disorders, I also think of sickle cell here (though perhaps not a true thrombophilia), PNH, APLA, hyperhomocysteine, as well as other causes that can be investigated. 

6. Infectious causes of stroke
- Discussed endocarditis
- Also VZV, TB, Nocardia, neurocysticercosis
- Rheumatic disease, or Chagas as cause for cardioembolism.

7. Rarer things
- Genetic disorders (MELAS, CADASIL), primary vasculitis less commonly present with stroke with exception of APLA.

The differential as can be seen needs to be expanded when a "young" patient has a stroke, history and physical will still guide you to effectively investigate and manage.

See this review article in the Lancet for details.

Thursday, October 31, 2013

Febrile Neutropenia

Quick post today from morning report where discussed a patient with a hematologic malignancy post chemotherapy presenting with fever and an absolute neutrophil count (ANC) of 0.3.

Remember that Febrile Neutropenia is a syndrome, not on its own a diagnosis, and we still need to do our job to find the cause/source.

Definition of Febrile Neutropenia is:
- Fever 38.3 x 1 or > 38 on multiple occasions (ie > 1 hour apart)
- Neutropenia (< 0.5 or < 1.0 with expected nadir less than 0.5)

Degree of neutropenia correlates with likelihood of developing fever, such that an ANC of 0.25-0.5 within approximately 7 days, there is ~30% chance of fever, and if ANC less than 0.25, 
chances can go up to ~90%.

Infection is always the concern, and a source will be found in approximately 30% of cases.

History and Physical (as always) is key! and remembering that these patients have no immune response reminds us that they might not have the ability to mount a dramatic inflammatory picture and so their signs/symptoms might be subtle.

Things to consider specifically:
- mucositis (oral, GI tract)
- dentition
- line: often these patients will have indwelling lines for chemotherapy. 
- abdominal findings
- subtle findings might warrant further investigation with imaging.

Full physical exam....
- inspect lines for: erythema, tenderness, purulent discharge (expressible?), induration, fluctuance
- DRE is contraindicated in patients with febrile neutropenia.

At risk organisms in general
- Gram negatives including Pseudomonas
- Gram positives especially if concerned with line infection
- C. Diffiicile, resistant organisms - depending on case.

Empiric therapy is aimed towards the above, and so often will consist of broad spectrum antibiotics including Pseudomonas coverage. Often times "double coverage" for Pseudomonas will be started, this is more for the concern that one of the agents might have resistance against it, so thus (hopefully) ensuring that one of the agents will work. 

Who gets Vanco? (not absolute, and certainly will vary depending on local micro patterns)
- concern for line infection
- known MRSA positive
- mucositis on prior fluoroquinolone proophylaxis (selects out for Viridans Group Strep with high MIC for penicillin).

When to stop?
- Consider stopping or stepping down once ANC normal, and afebrile x 48 hours
- Treat any identified source as you normally would

What if fever persists?
- if after day 4 fever continues consider antifungal coverage, especially if receiving prophylaxis

A word on typhlitis/neutropenic enterocolitis:

Mucous membrane damage can occur with chemotherapy (some more than others) which can lead to bacterial invasion of GI wall.
Major criteria for NEC would be
- Fever
- ANC < 0.5
- Bowel wall thickening > 4mm

These patients will have abdo pain, cramping, diarrhea.
Important to think about C.Diff in these patients in addition to above, and to get surgery consultation early if warranted. 

Full IDSA guidelines here. Remember that local micro patterns will alter protocols.

Wednesday, October 30, 2013

Myeloma kidney 

Multiple myeloma is a plasma cell dyscrasia, that will result in the production of pathogenic, abnormal paraprotein. 

Diagnosis is made looking for a paraprotein in the serum via an SPEP +/- IFE, the same can be done in the urine with a UPEP. Also serum free light chains and looking for the presence of Bence Jones protein in the urine is part of the workup. Bence Jones proteins are seen by mixing the urine sample with SSA that causes protein denaturation. This may be caused by the presence of albumin, but if the urine dip is negative for protein (specifically albumin), but mixing with SSA causes precipitation, then the is likely non-albumin protein (ie light chains).
Also remember that in renal failure, the serum free light chains will be elevated, not necessarily diagnostic, but what will be helpful is if the ratio is disproportionate.

There are many causes of renal disease with multiple myeloma. 

There can be 'indirect' harms: 

Hypercalcemia, and volume depletion.
Bisphosphonate therapy and kidney injury.
Possibly from recurrent infections.

Myeloma itself can cause direct damage to the different parts of the kidney: 

Tubulointersititial disease is common such as with myeloma kidney, acquired fanconi, and AIN. Glomerular disease can be seen with Ig deposition disease, AL amyloid, as well as cryo and GN.

Couple words on specific entities: 

“Myeloma kidney”  or cast nephropathy: 
Light chains in tubules. Can cause intrarenal obstruction as it precipitates. Fragmented casts seen on path.

Acquired Fanconi due to PCT dysfunction
Light chain disease causing inability to reabsorb glucose, uric acid, phosphate, bicarb, amino acids

Monoclonal Ig deposition disease: can be heavy or light. Proteins deposit into basement membrane causing disease. Like amyloid, can give extra renal manifestations.

AL amyloid: light chain forming amlyloid fibrils. Not all light chains are prone to fibrillogenesis, thus must be some form of mutation that predisposes. Look for extra renal manifestations as well. Requires tissue/histologic diagnosis.

Renal failure is often a poor prognostic sign and treatment is essentially aimed at reducing the production of the abnormal proteins and so is directed at the underlying myeloma. 

See this link for a review on myeloma and kidney disease by Korbet and Schwartz in 2006 in the JASN, also where the above image is from.

Thursday, October 24, 2013

Probably viral....right?

Morning report today presented the case of an otherwise well patient presenting with fever, dyspnea, cough, preceded by unilateral parotitis. 

The patient had a travel history to the middle east prior to presentation during which the symptoms developed. 

One diagnosis? Two? Occam's razor? Hickam's dictam?

DDx of parotitis:
Think about unilateral vs bilateral...although the rules often break down.

Unilateral is often due to a structural problem such as stones, or malignancy.
Stones can be massaged out and interestingly can be aided in expulsion by acidic environments ie lime or lemon juice. 

Bilateral causes (although can present unilateral)
- Infectious: mumps, viral (EBV, CMV, HIV flu, paraflu, rsv, hmpv), TB, lyme 
- Autoimmune: SLE, Sjogren's, sicca
- Inflammatory: secondary to bulimia nervosa

DDx of fever, dyspnea, cough 

Usual suspects
- Bacterial pneumonia
- Viral illnesses (see above)

but also consider if travel history consistent....

Novel influenza illnesses

MERS-CoV - Middle East Respiratory Syndrome - coronavirus
- first described in 2012
- 139 cases to date - France, Italy, Jordan, Qatar, Saudi Arabia, UK, UAE
- morality is reported anywhere from 30-50%
- details here from the CDC website

Public Health principles: isolate, personal protection, alert PHL

Back to the case....
On presentation appeared relatively well, but did require oxygen. NP swab was negative (including negative for MERS-CoV)...however bronchoscopy was positive for RSV.

In a retrospective cohort study by Bogoch et. al in 2013, they found that 6.9% of cases will have a negative NP swab, but will be positive on bronchoscopy.
See here for the article

A word on RSV:

Not just a pediatric virus, can infect adults.
While most people will recover outside of hospital, those that require admission can be very sick and people can die from RSV. Only to highlight to take this seriously.
NP swabs may be negative as the virus may have had contiguous spread to the lower tract.

Falsey et. al in 2005 published in the NEJM results of a prospective cohort study evaluating respiratory illnesses in the elderly and found that RSV accounted for similar rates of infection, hospitalization, ICU requirements, mortality as compared to influenza A.

Click NEJM RSV 2005 article  to view. 

Lastly...what about the parotid gland swelling?
On further history the patient endorsed dry eyes, dry mouth, serology came back as ANA positive and anti-La positive, and so was diagnosed as having Sjogren's syndrome.

Looks like Hickam was right in this case.

Wednesday, October 9, 2013

Fever in the returned traveller

Today in morning report we discussed a patient referred for fever.

The patient was otherwise well with no significant past medical history, not on any medications, no allergies, non-smoker. 

The patient had just returned from a trip, travelling with friends

This is a case of fever in the returned traveller.

Things to know:
   1.     Where did you go
   2.     When were you there (date arrived/left)
   3.     What did you do?
a.     Pre-travel: vaccines, pills (malaria proph).
b.     Travel: Itinterary!
                                               i.     Purpose: VFR (Visiting friends and relatives) – increased risk                   because (perhaps) less likely to seek pretravel advice, meds,                   vaccines, they lose innate immunity
                                              ii.     Urban vs rural
                                             iii.     Water: fresh/salt:
                   -   Fresh water fast moving – Lepto
                   -   Fresh water slow moving - schisto
                                             iv.     Bites
            a.     Mosquitos: malaria (Anopheles- night biters), dengue                     (Aedes- day biters), yellow fever
b.     Tic: ricketsial, lyme
c.     Sandfly (leishmaniasisi)
d.     Others include: mites, fleas (plague)

     v.   Exposures:
a.     Human: sexual
b.     Dogs/bats: rabies
c.     Other animals: goats, rodents
d.     Food: bottled water? Local
                                                                 -      Diarrheal bugs (salmonella typhi), hep A, unprocessed cheese (brucella)
   4.     Illness itself
-       Associated Symptoms
o   Retro-orbital pain: think dengue (+/- rash few days later)
o   Conjunctivitis: think leishmaniasis
o   Hematuria: think schisto
o   Resolving fever followed by terrible arthritis: Chikungunya (means “leaning forward”, because bent over with pain)
o   Rose spots, relative brady, diarrhea (sometimes constipation in adults) think typhoid

Our case:

Onset of fever 1 day before returning home. Generally unwell. Headache. 3 days later rash developed.

7 days abroad.  Water sports ie scuba. No fresh water exposure. No animal exposures. No sexual activity. Pre-travel received vaccinations for hepatitis A, yellow fever.

Diagnostic approach to FTR (Fever in the Returned Traveller): 
related infection vs unrelated infection vs not infection (ie VTE, drug fever)

Think about long incubation that may have been acquired prior to leaving OR short incubation that was acquired during trip

Influenza: short incubation period 12-48 hours
Hep A, B, C, HIV, longer incubation periods

Infections related to travel
**FTR is always malaria until proven otherwise: ie that you determine that malaria is not endemic in that area or 3x thick/thin smears negative. 

(malaria, typhoid, dengue, hep A account for ~80% of diseases from tropics)

Given the constellation of symptoms, the diagnosis here was Dengue.

-       most common mosquito borne illness
-       SA/Caribbean, SE asia
-       Aedes mosquito (day biters)
-       Urban
-       4 types 1,2,3,4
-       Once get one type of dengue will be immune. BUT if you get dengue with a second type,       higher (though still small) chance of bad complications
-       Retroorbital pain, bone pain are classic features, rash
-       Dengue hemorrhagic fever: low plt, plasma leakage
-       Measles mimics
-       Incubation time is ~7 days (often 3-4d)…after 14 days can feel like out of the woods.
-       Supportive management

   For more on FTR see this NEJM review article