12/14 PPMC Report: Wilson’s Disease

Today we discussed a really interesting case of Wilson’s disease. We all remember from medical school that Wilson’s disease is a problem with copper excretion:

Wilsons1.pngIn patient’s affected by this condition, the body’s normal mechanisms for excreting copper do not function appropriately, which leads to accumulation of free copper (and decreased ceruloplasmin), which then can get deposited in body tissues. The main sites that are affected are the liver, the cornea, and the brain. Neurologic manifestations of Wilson’s disease can include movement disorders, neuropsychiatric symptoms, and dysarthria. Corneal involvement is seen with presence of a Kayser-Fleischer ring. This disease can also be associated with a hemolytic anemia.

Degree of liver involvement can be variable, and in its most severe form can include acute liver failure. We reviewed criteria for acute liver failure:

Wilsons2

Of note, patients with Wilson’s disease and the top two criteria can still be considered acute liver failure even if there is underlying cirrhosis; this has important implications for status of transplant listing.

Wilson’s disease is suggested by low ceruloplasmin and elevated free copper in the blood. LFT abnormalities in a pattern of AST:ALT>2 and Alk Phos:T Bili <4 is also highly specific for this diagnosis.  In a less acute setting, copper chelators can be used for treatment. In acute liver failure, supportive measures can be helpful, and transplant is the definitive therapy. Plasmapheresis has also been reported in such cases!

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12/13 VA report: syncope, carotid dissection

Gracias to Sasha Deutsch-Link for presenting today: a middle aged veteran who came in with four episodes of syncope at rest.

We talked about the four major buckets of syncope:

  • Neurocardiogenic (aka vasovagal – ~20%)
    • Hx: prodrome (sweating, tunnel vision, stressors, emotion)
  • Orthostatic hypotension (10%)
    • Hx: lightheadedness or syncope on standing, recent h/o diarrhea, poor oral intake, etc
    • Causes: hypovolemia/diuretics, deconditioning, autonomic neuropathy (Parkinson’s, Lewy Body Dementia, POTS), DM, EtOH, amyloidosis, CKD
  • Cardiovascular
    • Hx: sudden LOC without prodrome, preceding palpitations, exertional syncope
    • Arrhythmia
      • Bradyarrhythmia: SSS, high-grade AV block, negative chronotropes, PPM malfunction
      • Tachyarrhythmia: VT, SVT, WPW
    • Mechanical:
      • Endocardial/Valvular: AS, MS, PS, prosthetic valve thrombosis, myxoma
      • Myocardial: pump dysfunction from MI or outflow obstruction from HCMP
      • Pericardial: tamponade
      • Vascular: PE, PHT, aortic dissection, ruptured AAA, subclavean steal
  • Neurologic (10%) – seizure, TIA/CVA, vertebrobasilar insufficiency, dissection of cerebral arteries, migraine, narcolepsy
  • Misc: hypoglycemia, hypoxia, anemia, psychogenic
To do in everyone
  • Careful volume and neuro exams
  • Medication review to identify potential culprits (alpha blockers, nitrates, diuretics, antipsychotics, antiarrhythmics, BBs and CCBs)
Tests to consider
  • EKG
  • Troponin (if suspect PE or ACS as cause)
  • ECHO – to rule out structural heart disease
  • Exercise treadmill test – esp with exertional syncope, r/o ischemia
  • Neuro studies (CT, MRI, EEG) – if history is suggestive
High Risk Features (which may warrant admission)
  • Age >60
  • h/o CAD, HF/CMP, valvular or congenital heart disease, arrhythmia
  • Syncope c/w cardiac cause (lack of prodrome, exertional, resultant trauma) or recurrent
  • Complaint of chest pain or dyspnea, abnormal vitals or cardiac exam
  • PPM/ICD in place, abnormal EKG

We also talked briefly about carotid dissection:

  • Occurs more commonly in the extracranial carotids
  • Traumatic
    • MVC, rapid deceleration injuries, TBI; also implicated: vomiting, yoga, painting a ceiling, neck manipulation during anesthesia, ?chiropractor visits, ?respiratory infections
  • Spontaneous
    • Risk fx: Ehlers-Danlos, Marfan’s, osteogenesis imperfecta, AD
  • Can present with neck pain, CN (commonly XII) deficits, pulsatile tinnitus or stroke symptoms
  • Dx: MRA, CTA > carotid U/S (lots of false positives)
  • Tx: depends on the extent of the lesion and any accompanying deficits, but can require surgery vs medical management (anticoagulation/antiplatelet therapy, angioplasty)

References

  1. Patel R et al. Cervical Carotid Artery Dissection: Current Review of Diagnosis and Treatment. Cardiology in Review 2012.

12/13 PPMC Report: Granulomatosis with Polyangiitis

Thank you to Dr. Johr for joining us as a faculty expert to discuss a new diagnosis of granulomatosis with polyangiitis (GPA). The patient was a 19 year old previously healthy male who initially presented with variable upper respiratory and lower respiratory symptoms for a few months with multifocal pulmonary infiltrates refractory to antibiotics, who then developed glomerulonephritis with acute renal failure.

One important take-away from this case is to always think broadly about the differential without anchoring, and to make sure that your clinical decision-making takes your patient’s demographic and medical background into account. Our patient was a healthy 19 year old male who developed persistent otitis media, followed by persistent laryngitis and then lower respiratory symptoms with imaging demonstrating multifocal opacities. He also had constitutional symptoms and a urinalysis with large blood. He was treated at this point for community-acquired pneumonia — this diagnosis was likely an instinctive reaction to pulmonary consolidations and lower respiratory symptoms, but a previously healthy young male is not the typical host for CAP; furthermore, this diagnosis fails to take the patient’s other presenting signs and symptoms into account.

We discussed the differential for pulmonary-renal syndromes. It is not very long! While it is possible that the pulmonary and renal components demonstrate different disease processes, in most cases pulmonary-renal syndrome is secondary to ANCA-associated vasculitis (MPA, GPA, eGPA), Goodpasture’s (anti-glomerular basement membrane), or other rheumatologic conditions (SLE). Our patient’s clinical history of upper airway disease and his presentation with pulmonary-renal syndrome was clinically very strongly concerning for GPA, and his serologies were consistent with this diagnosis (positive anti-PR3 and c-ANCA).

“ANCA” stands for anti-neutrophil cytoplasmic antibody — these can be positive in a number of conditions, even IBD! Recently, identification of a specific anti-nuclear antibody (ie either anti-MPO or anti-PR3) has become increasingly clinically relevant. As we have discussed previously on this blog in our PAN case, vasculitis is inflammation of the vessels and is typically classified based on size of involved vessels. Small-vessel disease can be sub-categorized by disease mechanism into those caused by immune complex deposition, and those caused by presence of ANCA. Figure below from Jennette et al, Arthritis and Rheumatology.

PAN1

GPA is classically characterized by upper airway involvement and constitutional symptoms, and can commonly have renal involvement as well. This disease can also cause subglottis stenosis, which can be life-threatening and incredibly difficult to treat.  It is usually associated with positive anti-PR3 and c-ANCA.

Treatment strategy depends on severity and organ involvement, and also on the patient’s demographics and comorbidities. In general, induction therapy involves a combination of high dose glucocorticoids and either cyclophosphamide or rituximab. In severe cases, plasma exchange can also be used. Treatment also involves a maintenance phase.

References:

Jennette JC et al. 2012 Revised International Chapel Hill Consensus Conference Nomenclature of Vasculitides. Arthritis Rheum 013; 65:1.

 

12/7 HUP Report: Disseminated Cryptococcus

Thanks to Dr. Barton for being our faculty expert today to discuss a case of disseminated Cryptococcus! The patient we discussed today did not have the usual risk factors for this infection, which we typically think about in patients who have compromised cellular immunity. Particular patient populations at risk include patients with HIV, hematopoietic stem cell transplant recipients, and solid organ transplant recipients.

Cryptococcus is a budding yeast with a capsule, seen here on silver stain:

CR1                                   http://englishdictionary.education/en/cryptococcus

The most common sites of Cryptococcus infection are the lungs and the CNS. It can also cause skin infection, particularly in HIV patients, which can resemble molluscum in appearance. If Cryptococcus is cultured from any other organ, it should be treated as disseminated infection.

CR2

https://www.researchgate.net/figure/232279838_fig2_Figure-1-The-dissemination-model-of-Cryptococcus-neoformans-from-the-environment-to-the

Although disseminated Cryptococcus and cryptococcal meningitis should be treated with the same medications, it is still important to perform an LP in someone with cryptococcemia to check opening pressure — it is frequently elevated in patients with CNS involvement of disseminated Cryptococcus, which can have serious consequences and may require treatment with CSF removal.

Below are guidelines for treatment of disseminated Cryptococcus in non-HIV non-transplant hosts, from the Infectious Disease Society of America. Basically, there are three stages of treatment: induction, consolidation, and maintenance. The induction phase should involve a combination of amphotericin and flucytosine, followed by consolidation with high dose fluconazole and maintenance with lower dose fluconazole.

CR3

See below for a reference of a case report similar to our own patient!

References:

Okamoto K, Proia LA, Demarais PL. Disseminated Cryptococcal Disease in a Patient with Chronic Lymphocytic Leukemia on Ibrutinib. Case Rep Infect Dis. 2016;2016:4642831. Epub 2016 Sep 14.

 

 

12/4 Presby report: relapsing fevers, EBV serologies

A big thanks to Robin for presenting the case of an older man who developed high fevers that disappeared and then relapsed, along with cytopenias and LFT abnormalities, and was ultimately diagnosed with Anaplasma. There was a lot of rich discussion during this case!

What defines a fever?

  • Normal body temperature fluctuates throughout the day, with temps lower in the morning (max 98.9F) and higher in the evening (max 99.9F)
    • so whether you call something a fever or not may depend on the time of day; the cutoff of 100.4F that we’ve come to use is in some ways quite arbitrary

There’s no strict definition of ‘relapsing’ fever; there just has to be some fever-free interval (generally at least 24-48h) before the fevers start again.

  • Keep in mind that several etiologic organisms cause fevers in a relapsing pattern, and that there is also an entity called ‘relapsing fever’ which is caused specifically by several Borrelia species

Causes of relapsing fever

  1. Tick-borne relapsing fever (TBRF): caused by Borellia spp (parkeri, turicatae, hermsii) and transmitted by SOFT ticks like Ornithodoros (different from hard ticks like Ixodes which transmit Lyme, Babesia, etc). Main risk factor: rodent exposure
  2. Louse-borne relapsing fever (LBRF): caused by Borellia recurrentis and transmitted by human body louse. Mostly limited to Africa.
  3. Borellia miyamotoi: a newly described pathogen, transmitted by hard ticks which can be contracted in the Northeast US
  4. Leptospirosis
  5. Rare: anaplasma, ehrlichia
  6. Malignant fevers, particularly Pel-Ebstein fevers from Hodgkin’s lymphoma

 

Lastly, we talked about EBV serology interpretation. Remember that most people get EBV in childhood.

EBV testing has three components: viral capsid antigen (VCA) IgG, VCA IgM and Epstein-Barr Nuclear Antigen (EBNA)

  • The EBNA will stay elevated indefinitely after infection, so if it’s elevated, that indicates past infection
  • If the VCA IgM is elevated and EBNA is not, that likely indicates recent infection
  • The VCA IgG is really ‘corroborative’ and remains elevated after past infection

 

Screen Shot 2017-12-07 at 10.13.32 AM.png

Interpretation of EBV serologies

Screen Shot 2017-12-04 at 1.28.55 PM.png

Source: Mayo Medical Laboratories. Note: *Results indicate infection with EBV at some time (VCA IgG positive). However, the time of the infection cannot be predicted (ie, recent or past) since antibodies to EBNA usually develop after primary infection (recent) or, alternatively, approximately 5% to 10% of patients with EBV never develop antibodies to EBNA (past).

 

References

  1. Barbour A. Harrison’s Principles of Internal Medicine. “Relapsing Fevers”.

12/5 HUP Report: An unusual case of TTP

Today we discussed an unusual case of TTP, and along the way we reviewed the differential for hemolytic anemia and Evans Syndrome in particular. Thank you to our faculty expert, Dr. Cuker, for some amazing teaching! Our patient was a young female previously treated for melanoma who developed thrombocytopenia and hemolytic anemia. There are different frameworks in which to classify hemolytic anemias. Today we thought about immune vs. non-immune mediated processes (which is not perfect, and some etiologies can fall within both categories!). Here is some of the differential that we discussed:

TTP1

Direct antibody test can be used to determine if there is antibody or complement bound to the patient’s RBCs. In this test, the patient’s RBCs are separated out from the serum and incubated with anti-human IgG; if there is antibody or C3 bound to the patient’s RBCs, then agglutination will occur, resulting in a positive test result. Indirect antibody testing looks at the patient’s serum to test for antibodies to RBCs – the serum is incubated with other RBCs (ie not from the patient), and then anti-human IgG  is added. If the serum contains anti-RBC antibodies, they will bind the cells and then agglutination will occur when anti-human IgG is added. (Figure adapted from Wikipedia.org)

TTP2.png

Our patient was initially thought to have Evans Syndrome, which is a condition that involves at least two immune-mediated cytopenias, most commonly thrombocytopenia and hemolytic anemia. Corticosteroids are usually the first line of treatment, especially if the patient is presenting with anemia. If the patient is presenting with thrombocytopenia as the primary concern, then IVIg can be considered. These patients typically have relapsing courses, and this can be really difficult to treat.

Our patient initially did really well with steroids, but then had recurrence of thrombocytopenia and hemolytic anemia, this time accompanied by abdominal pain and a peripheral smear with many schistocytes, which had not previously been seen. She was ultimately diagnosed with TTP, which is a form of thrombotic microangiopathy caused by low ADAMTS13 level. In healthy patients, ADAMTS13 cleaves ultralarge Von Willebrand Factor multimers, so when activity is low these multimers can persist. This causes platelet activation and aggregation, which can lead to thrombosis and ischemia to end-organs, and a hemolytic anemia from shearing.

TTP3.png

Treatment for TTP has made a dramatic change in mortality of this condition. Patients with suspected TTP should be treated immediately! Plasma exchange should be initiated as soon as possible, along with corticosteroids. There is also growing evidence to support use of rituximab in all patients without contraindications; this can be removed by plasma exchange, so should be dosed following sessions when possible.

References: please see citations underneath figures

 

 

 

 

 

 

 

 

11/30 HUP Report: Polyarteritis Nodosa

Today we were joined by a world expert in vasculitis, Dr. Peter Merkel, to discuss an interesting case of a young female who presented with foot drop and necrotic skin lesions.

This constellation of symptoms can be caused by a few different disease entities, but we focused our discussion on vasculitides. Vasculitis is typically characterized by which size of vessel is affected by the inflammation process (Jennette et al, Arthritis Rheum):

PAN1.pngOur patient’s skin biopsy showed small/medium vessel vasculitis, and work up was notable for negative ANCA and other serologies. Clinically, this presentation was concerning for polyarteritis nodosa, which is a necrotizing vasculitis that typically affects medium-sized vessels. Common presenting symptoms include general malaise, myalgias/arthralgias; renal involvement is also very common, and skin lesions can be seen. Notably, pulmonary involvement is very uncommon. The following figure has been adapted from http://www.rheumaknowledgy.com.

PAN2.pngTreatment depends on severity of presentation and major organ involvement. Glucocorticoids are a cornerstone of treatment; combination immunosuppression may be necessary in severe cases, with many providers using a regimen of glucocorticoids and cyclophosphamide. Methotrexate, azathioprine, mycophenolate and rituximab have also been studied in this disease. Individual patient factors may need to be considered in treatment decisions too.

Data on treatments is limited since this is a very rare disease, and historically diagnosis criteria has changed making the patient population of interest more difficult to define. The study below (Gayraud et al, Arthritis and Rheumatism) retrospectively analyzed data from n=278 patients with PAN, MPA, or eGPA who had previously been enrolled in four different prospective studies looking at different treatment protocols. They found that in comparison to the general population (of France, where the study was conducted), patients with vasculitis had increased mortality – not surprisingly.

PAN2.pngThey also found that when stratified by severity of disease, patients with more severe disease who had been treated initially with a combination of glucocorticoids and cyclophosphamide had better outcomes than those treated with glucocorticoids alone.

PAN3

References:

Jennette JC et al. 2012 revised International Chapel Hill Consensus Conference Nomenclature of Vasculitides. Arthritis Rheum. 2013 Jan;65(1):1-11. doi: 10.1002/art.37715.

Gayraud M et al. Long-Term Followup of Polyarteritis Nodosa, Microscopic Polyangiitis, and Churg-Strauss Syndrome. Arthritis Rheum. 2001 Mar;44(3):666-675.