Day #31 - Fever of Unknown Origin

Today we discussed a case of true fever of unknown origin.

Epidemiologic Criteria:

• Fever x 3 weeks (38.3)
• Failure to find cause despite appropriate initial outpatient/inpatient investigations

Causes:

• Majority unknown
• Then infection (most commonly TB or occult abscesses), inflammatory, malignancy, other

Diagnostic tests (beyond initial):

• CT abdomen to look for abscess, lymphadenopathy, other pathology. Yield ~20%
  
• Bone scan (insensitive, but specific with good + LR)
• Liver biopsy -- regardless of hepatomegaly or LFT abnormalities has yield ~15%
• Temporal artery biopsy in the elderly -- yield ~ 15%
• Leg dopplers -- yield 2-6%
• Bone marrow biopsy-- in those with cytopenias or compatable syndromes. Yield ~1%

Day #30 - Transient Ischemic Attack

Today's case was an acute stoke with rapidly resolving deficits. We discussed localization of infarcts and localized this case to the midbrain based on the constellation of deficits.

The following images are helpful in reviewing the sensory and motor pathways.



In patients with TIAs there is a definite risk of ~10% in the next 90 days of having a stroke. Studies suggest that 1/2 of this risk happens in the first 3-7 days. Consequently, a TIA should be thought of as a medical emergency warranting risk factor modification and assessment for treatable cause (i.e. atrial fibrillation, >70% ipsilateral carotid stenosis). However, not all transient neurological symptoms are TIAs! We need some means of selecting which patients are most likely to actually have a stroke so we can focus our efforts on them.

Several attempts have been made to help determine which patients with TIA are most likely to have a stroke. The one I like is the ABCD2 score.

A - Age Greater than 60 == 1 point
B - BP >140 in ER == 1 point
C - Clinical Features: Weakness == 2 points, Speech problem == 1 point, other == 0
D - Duration: >1hr ==2 points, 15-60mins = 1 point, <15 mins = 0 points
D - Diabetes == 1 point

Low Risk = 0-3 points -- 1.0% had stroke in 2d, 1.2% in 7d, 3.1% in 90d
Medium Risk = 4-6 -- 4.1% in 2 d, 5.9 in 7d, 9.8% in 90d
High risk = Greater than 6 -- 8.1% in 2d, 12% in 7d, 18% in 90d

Consider that crescendo TIA is a different story and this model does not apply to patients with crescendo TIAs.

In general low risk patients can be treated as outpatients with risk factor modification and investigations.

Medium risk patients probably can be treated with expedited investigations and risk factor modification. This will depend on the clinical context. For example a 40 year-old patient with 3 hours of objective weakness would score 4, but probably should be more urgently investigated.

High risk patients should probably be admitted for urgent investigations and for monitoring for indications for acute thrombolysis should stroke occur.

Day #29 - Demand Ischemia

Today we talked about a case of a young man who essentially presented with status epilepticus and was found to have some non-specific ECG changes, a CXR compatible with CHF though without evidence of CHF on clinical exam, and an elevated cardiac troponin.

The discussent, a cardiologist, facilitated a good discussion on the approach to a patient with seizures including considering that what was labelled "seizure" may, in some patients with underlying cardiac dysrthmias or ischemic/structural heart disease be a presentation of primary cardiac abnormalities.

In this patient, who subsequently turned out to have a normal baseline ECG and a normal 2D echo and who will go on to angiography, the suspicion is that this troponin increase was caused by severe myocardial demand during the status epilepticus. The combination of catecholamine surge, increased muscle tone leading to increased afterload, and tachycardia presumably led to sub-endocardial ischemia.

There are conflicting case reports about whether seizures themselves can lead to troponin increases with one small patient series saying no, and several single patient case reports saying yes. I think the take home message from this is that you can't write off significantly elevated troponins as being entirely due to the seizure.

We spent some time discussing stress-induced cardiomyopathy or apical ballooning syndrome. There are some case reports of status epilepticus causing this syndrome (in one of these cases the troponin was elevated to 10!).

Also, if you haven't done so already, I would suggest you review the blog on seizures/status epilepticus.

Day #28 - Thrombocytopenia

Today we talked about a case of an elderly man who presented with isolated acute, relatively asymptomatic, severe thrombocytopenia.

We discussed an approach to the differential diagnosis of thrombocytopenia:

• Decreased production: i.e. myelodysplasia, leukemia/lymphoma, other infiltrative malignancy (i.e. breast cancer), substrate deficiency (B12/folate), toxins (ETOH, methotrexate, chemo), infections (measles, mumps, rubella, EBV),
  
• Sequestration in the spleen
  
• Increased destruction:
  
  • Immune mediated: collagen vascular disease including SLE and APLA, viral - HIV/HBV/HCV/EBV/CMV, Idiopathic Thrombocytopenia Purpura, drug related - i.e. vancomycin/septra/quinine, heparin induced thrombocytopenia (HIT), post-transfusion purpura
    
  • Non-immune mediated: DIC, TTP/HUS, HELLP syndrome, sepsis
    
• Congenital/Gestational

We used this differential to focus our history and physical exam, then used that information recursively to make come up with an investigation plan.

After reviewing the lab tests including bone marrow biopsy we decided that the most likely diagnosis in today's case was ITP and then touched upon treatment. There are guidelines on treatment published but these date back to 1997.

NB: Patients should be immunized against pneumococcus, haemophilus, and neiserria species on diagnosis in case splenectomy is required.

Treatment for ITP

1. When: Risk of bleeding complications is greater than the risk of treatment
   
   • Is there severe or life threatening bleeding ==> TREAT
   • Is the risk of bleeding high because PLT <10> TREAT
   • Is the PLT count <30-50?
     
     • Bleeding? ==> TREAT
     • Asymptomatic but risk of bleeding due to lifestyle or other conditions ==> consider TREATING, discuss with patient
       
   • Is the PLT count >30-50 ==> Observe
2. How:
   
   • Steroids:
     
     • Prednisone 1mg/kg PO OD -- should work within 1-2 weeks. If not consider other method. Taper over 4-6 weeks after PLT count normalized
     • Dexamethasone 40mg PO OD x 4 days -- repeat in 14-28d as needed to complete 4-8 "cycles". Head to head trial with prednisone is underway
     • Pulse solumedrol -- small studies suggest benefit, large studies pending
       
   • IVIG -- 1g/kg/day x 1-2 days. Response in a few days, duration several weeks
   • Second line therapy:|
     
     • Splenectomy -- 4-6 weeks of treatment should happen first to allow for spontaneous remission. Will induce remission in ~ 65%. Risk of overwhelming post splenectomy infection (OPSI) of ~ 1/1000 per year.
     • Rituximab -- insufficient evidence to recommend. Use limited to patients with an unacceptably high risk from splenectomy
   • Refractory ITP (Plt <50,> 3 months, failed splenectomy)
     
     • Specialty consultation required. Consider observation, chronic steroids, rituximab, cyclophosphamide, other immunosuppressives/modulatories
     
     

Meningitis

The meningitis lecture from today is available here.

Day #25 - Adrenal Insufficiency

Today we talked about a case of a woman with a history of chronic steroid use who presented with refractory hypotension and hypoglycemia in the context of a systemic infection. The team were highly suspicious that this represented adrenal insufficiency in the context of a stressor. I wanted to touch upon how one can make the laboratory diagnosis of adrenal insufficiency.

The first step is to obtain morning (8AM) measurements of cortisol and ACTH.

• If the cotisol is below 80nmol/L the diagnosis is confirmed. If the ACTH is high, this suggests primary adrenal insufficiency, if the ACTH is inadequate this suggests secondary or tertiary adrenal insufficiency
  
• If the cortisol is above 500nmol/L the diagnosis is essentially excluded.
• If the cortisol is between 80-500, dynamic testing is required

The downside is that ACTH takes a long time to come back, and often you don't want to wait until 8am to make the diagnosis.

Dynamic testing (can happen at any time of day when the lab is open):
Obtain baseline cortisol measurement.
Then administer cosyntropin 250mcg IV
Then obtain cortisol measurements at 30 and 60 minutes post injection

If the cortisol increases to >550nmol/L then primary adrenal insufficiency is excluded and probably secondary as well -- although not definitively. If you have a high index of suspicion for secondary or tertiary adrenal insufficiency you should probably consult an endocrinologist as you will need specialized testing (i.e. CRH stimulation test, insulin induced hypogylcemia test, metrapyrone test)

In suspected adrenal crisis, you should obtain a STAT cortisol and ACTH measurement then start treatment with steroids and IV saline. Dexamethasone is preferable because it won't be picked up on the cortisol assay and consequently you can continue treatment while working up the patient. Remember that dexamethasone can suppress ACTH release, and so you will need to do dynamic testing unless the baseline studies are diagnostic.

Day #24 - Colitis

Today we discussed a gay male with fever, abdominal cramping, tenesmus and bloody diarrhea. The discussant made a very important point -- the clinical context and history are very important in making the diagnosis in acute colitis.

Before making the diagnosis of IBD one should exclude infections by history and special tests. Infections can mimic IBD clinically, radiographically, and endoscopically.

I wanted to talk about the differential diagnosis of bloody diarrhea with fever.

Differential Diagnosis

Infectious

• Enteroinvasive infection: Salmonella, Shigella, Campylobacter, E. Coli 0157:H7 (associated with HUS, frequently afebrile), Clostridium difficile, Klebsiella oxytoca
  
• Associated with receptive anal intercourse: HSV proctitis, gonorrhea, chlamydia (L serovar - AKA LGV/lymphogranuloma venerium), syphilis
  
• Associated with oral-anal practices or colonic irrigation: intestinal amebiasis
• More chronic, associated with the terminal illeum: intestinal tuberculosis
• Immunosuppressed patients: CMV colitis
  

Inflammatory

• Ulcerative colitis/Crohn's disease
  

Ischemic Colitis

There is also a good case of a patient with fever and diarrhea in the NEJM available here.