Intravascular Lymphoma

Motivation: Zebras are growing more frequent these days.  Though thought to be quite rare, I have seen two of my favorite patients diagnosed with intravascular lymphoma within the past year.  In both, the diagnosis could not be made for months because of the non-traditional lymphoma findings - for instance, no enlarged lymph nodes.  Intravascular lymphoma is characterized by growth of lymphoid neoplastic cells with the lumen of blood vessels.  Given lack of systemic masses, are there clinical clues to its diagnosis?  We will review here one of the largest review of cases for this rare disorder.

Paper: Ferreri, A.J.M., Campo, E., Seymour, J.F. et. al. "Intravascular lymphoma: clinical presentation, natural history, management and prognostic factors in a series of 38 cases, with special emphasis on the 'cutaneous variant'" Brit. J. of Haematol. (2004); 127: 173-183

Methods: Data gathered from 22 centers forming the International Extranodal Lymphoma Study Group (IELSG) on patients who were  HIV negative and were diagnosed with intravascular lymphoma between 1985 and 2003.

Results: 
Cohort: Intravascular lymphoma was diagnosed in 38 patients - postmortem in eight (21%) and while living in 30 (79%).  The median age was 70 years with male/female ratio of 0.9.

Clinical Presentation: The most common presenting symptom was fever in 45%.  Systemic symptoms including fever, weight loss, or night sweats were present in 55%.  Cutaneous lesions were present in 39% made up of a wide variety of lesions including erythematous eruption, plaques, swelling, nodular discolorations, or small red palpable spots situated in upper arms, thighs, legs, lower abdomen, or breast.  The next most common finding was neurological symptoms present in 34% with a wide range of symptoms from focal deficits to meningoradiculitis.

Laboratory Variables: The most common lab abnormality was elevated serum LDH (86%) followed by elevated beta-2 microglobulin (82%).  ESR was elevated in 43%.  Anemia was present in 63% while leukopenia and thrombocytopenia were present in 24 and 29% respectively. 

Discussion: Intravascular lmphoma remains a difficult disorder to diagnose.  I think that patients with unclear lesions in the brain and skin with systemic symptoms should raise suspicion of intravascular lymphoma.  The present large series also contrasts with previous reports from Japan where intravascular lymphoma presented more commonly with hemophagocytic syndrome and less commonly with cutaneous or neurological symptoms suggesting that there may be ethnic variance versus diagnostic bias in the previous report.  Laboratories are helpful for elevated beta-2 microglobulin present in more than 80%.  In summary, I learnt that if I suspect patient of having intravascular lymphoma in the brain, I will conduct a skin exam.  

Cefepime Encephalopathy

Motivation: My favorite fourth generation cephalosporin is cefepime.  Only a definite history of anaphylaxis to penicillins holds me back from prescribing cefepime.  More recently, I have met a few patients with confusion allegedly caused by cefepime.  Amazingly, stopping the cefepime improved the encephalopathy.

So, what is wrong with my favorite cephalosporin?  The literature on cefepime neurotoxicity is evolving and is still at the case report level.  Reviewed here is a case report and literature summary.

Paper: McNally, A., Pithie, A., and Jardine, D. "Cefepime: a rare cause of encephalopathy." Internal Medicine Journal (2012); 42 (6): 732-3.

Method: Case report and review of published literature.

Result: 
Case report:  A 70 year old woman after eleven days of cefepime for Pseudomonas osteomyelitis developed myoclonus and stupor.  Concurrently, patient also suffered from hepatic cirrhosis and acute on chronic renal failure.  For presumed drug toxicity, cefepime and all psychotropic drugs in patient's regimen (including morphine, gabapentin, oxazepam) were stopped.  Over three days, encephalopathy and myoclonus resolved.  Patient was re-challenged with cefepime at renal-adjusted dose.  Encephalopathy and myoclonus recurred in the next two days despite now resolved renal failure and normal ammonia.  Cefepime was stopped, and patient's encephalopathy cleared.

Literature Review: Eetrospective review of 42 cases showed that encephalopathy consisted of temporospatial disorientation (96%), myoclonus (33%), and seizures (13%).  The clearest association of cefepime toxicity exists with renal impairment though cefepime toxicity has also been described in patients with normal renal function.  The reported latency of symptoms from cefepime initiation is 1-10 days.  After stopping cefepime, symptoms regress over 2-7 days.

Discussion:
While the case for cefepime toxicity in this case report is weakened by concurrent hepatic and renal failure, the history of encephalopathy linked temporally with cefepime initiation along with improved mental clarity with cefepime cessation makes a good causal argument for cefepime causing encephalopathy.  There do not appear to be symptoms characteristic of cefepime neurotoxicity though seizures and myoclonus are frequent occurrences.    Without a larger case series, it is hard to attribute causality to cefepime.  On the other hand, if a patient with renal failure on cefepime develops confusion, I would recommend cefepime cessation (despite my personal attachment to the drug).

Tennis Elbow - Work or Rest or Steroids

Motivation: Summer is the time for tennis and tennis elbow.  Anyone who has suffered a tennis elbow - known in medial lingo as lateral epicondylalgia -  can attest to the frustration and pain that keeps people away from the beautiful sport after waiting all winter.  I have often wondered what works.  Using an injured elbow hardly seems wise but then again, exercise sounds like a good idea.  If all else fails, do steroid injections work?  Recently, this idea was tested in a randomized way.

Paper: Coombes, B.K., Bisset, L., Brooks, P. et. al. "Effect of Corticosteroid Injection, Physiotherapy, or Both on Clinical Outcomes in Patients with Unilateral Lateral Epicondylalgia." JAMA (2013); 309(5): 461-469.

Methods: 2x2 factorial multi-center randomized blinded placebo controlled trial.  Inclusion critera were essentially untreated unilateral lateral elbow pain of greater than six weeks duration provoked by palpation or stretching the region.  The two intervention arms were a single corticosteroid (triamcinolone) vs. placebo injection and physiotherapy for eight weeks vs. no physiotherapy.  The primary outcomes were one year rating of change score (using Likert scale from "complete recovery" to "much worse") and one year recurrence.  Secondary outcomes were rate of complete recovery to much improvement at four and 26 weeks.

Results:
 Cohort: A total of 165 patients were randomized with mean age of 49 years and male predominance of 62%.  Average duration of symptoms was 16 weeks. On visual analog scale (VAS), resting median pain level was 7.5 out of 100 with worst pain of 61.7 out of 100.  In total , 41 patients only got placebo, 41 got placebo plus physiotherapy, 43 got corticosteroids, and 40 got corticosteroids plus physiotherapy.

Primary Outcome (one year): Corticosteroids resulted in lower recovery or improvement at one year compared to placebo (83% with steroids vs. 96% without, p = 0.01).  There was increased recurrence of elbow pain at one year with corticosteroids (54% with steroids vs. 12%, p < 0.001).  There was no difference between physiotherapy or no physiotherapy in terms of recovery or rate of recurrence.  There was no interaction between corticosteroids and physiotherapy.

Four week Outcome: In absence of physiotherapy, complete recovery or much improvement was greater following steroid injection than placebo (RR: 7.32, NNT 1.6, p < 0.001).  With physiotherapy, steroids did not significantly improve recovery compared to placebo (RR: 1.73 (95% CI, 0.97 to 3.08)) though combination had some additional benefit on pain scores.  Physiotherapy alone in absence of steroids also significantly improved recovery (RR: 4,.0, NNT: 3.4, p = 0.004).  There was no major difference between steroids plus physiotherapy versus steroids alone.

Discussion: This paper points out an instance where trials with short term follow-up miss deleterious effects in the long term.  Steroids are quite efficacious in four weeks but result in greater recurrence of pain and with lower recovery in one year.  In comparison, while physiotherapy does not make a difference in the long term, it is comparable to steroids for recovery at four weeks.  Consequently, for someone with a tennis elbow, a reasonable strategy would be to use physiotherapy in the short term and expect spontaneous recovery in the long term (96% recovery naturally) - avoid the steroids.

Albuterol, levalbuterol and tachycardia

Motivation:  In the ICU and inpatient setting, tachycardia is a common vital sign abnormality that has many different root causes. One of the measures taken in attempt to decrease heart rate is to limit beta-agonists such as inhaled or nebulized albuterol, a common medication used for the shortness of breath or wheezing experienced by many patients. One solution that has been suggested to me was to use levalbuterol instead of albuterol...Physiologically it makes sense that albuterol or levalbuterol would increase heart rate, but I was not sure about any physiological/molecular reason why levalbuterol would be associated with less tachycardic side effects, and was also concerned about levalbuterol's higher cost. So does albuterol really contribute to increased tachycardia, and would levalbuterol be a better option?

Study:  Khorfan FM, Smith P, Watt S, Barber KR. Effects of nebulized bronchodilator therapy on heart rate and arrhythmias in critically ill adult patients. Chest. 2011 Dec;140(6):1466-72.

Methods: This was a 2:1 randomized, prospective, single-blind crossover study in 70 adult ICU patients who were randomized to alternating 4-6 hour courses of nebulized albuterol (2.5 mg) or levalbuterol, along with ipratropium. Group A received 0.63 mg, while Group B received 1.25 mg of levalbeterol. Cardiac monitoring was performed to measure heart rate and rhythm before, during and after treatment.

Results: The 70 patients consisted of almost equal numbers of men and women, with age ranges from 35-92, and slightly more than half on mechanical ventilation. Multisystem organ problems were common in this population. The median number of treatments per patient was 23, ranging from 1 to 45. There was no significant difference in change in heart rate after albuterol (0.89 ± 4.5 bpm) or levalbuterol (0.85 ± 5.3 bpm) treatment in Group A. In Group B, levalbuterol actually was associated with faster heart rate (increase of 1.4 ± 5.4 bpm) compared to albuterol (decrease of 0.16 ± 5.1 bpm) (p=0.03); but when analyzing for measures that were taken >= 5 hours apart, this difference was no long statistically significant. There was only one patient who had to be discontinued on treatment, after experience a 5 beat run of NSVT after 6x albuterol treatment.

Discussion: As for levalbuterol, its substitution for albuterol was not justified in this study - in fact, in Group B, in which a higher levalbuterol dose was used, post-therapy heart rate was actually faster than post-albuterol heart rate. Unexpectedly, from this study, it seemed that albuterol or levalbuterol did not significantly worsen tachycardia, even in this very sick population of patients. This is useful - and comforting - to know for patients who are tachycardic, but also have wheezes or increased airway resistance who would benefit from temporary courses of nebulized beta-agonists. One limitation of the applicability of this study is the fact that heart rate comparisons were made only after a limited number of treatments per patient, so it could be possible that over longer term and more treatments +/- higher frequency +/- higher dosing, there would be significantly increased heart rate. So in a patient receiving longer term albuterol therapy, I would still consider tapering down or decreasing albuterol therapy if tachycardia were a problem, since this would make sense physiologically.

VZV Vasculitis

Motivation: This year, I have seen quite a number of middle aged otherwise healthy patients present with shingles.  Usually, initial questioning leads to some complaints of headaches, which results in a lumbar puncture showing a few cells.  Now the possibilities open.  Could the patient have VZV vasculitis?  I was once asked this question, and I had no clue what VZV vasculitis looked like.

Paper: Nagel, M.A., Cohrs, R.J., Mahalingam, R., et. al. "The varicella zoster virus vasculopathies." Neurology (2008); 70: 853-860.

Methods: Review of thirty patients (previous published cases and unpublished cases) with serologic or PCR proof of positive VZV and neurologic signs or symptoms attributed to VZV infection by the reviewing authors.

Results:

Cohort: Of the thirty patients, the age ranged from one year to 88 years with fifty percent of patients male and the rest female.  Of the thirty patients, eleven patients had important comorbid disorders - 2 with AIDS, 3 with HIV, 2 with leukemia, 1 with CREST syndrome, 1 with lymphoma, 1 with decreased CD4 count, and 1 on immunosuppression for lupus and rheumatoid arthritis.

Clinical Features: In total, of 30 patients, nineteen (63%) had rash, twenty (67%) had CSF pleocytosis of >5 wbc.  Average interval between onset of rash and neurological symptoms was 4.1 months.  Of the eleven immunocompromised patients, six (54%) had rash, nine (82%) had CSF pleocytosis, six (54%) had positive VZV PCR, and eleven (100%) had anti-VZV IgG antibody.  In the 19 immunocompentent, thirteen (68%) had rash, eleven (58%) had CSF pleocytosis, three (16%) had positive PCR, and seventeen (89%) had positive anti-VZV IgG in CSF.  PCR was positive more frequently in the immunocompromised.  Of note, all patients with CSF anti-VZV IgG had reduced serum to CSF ratio.

Imaging:  Of the entire cohort, 29 (97%) had abnormal brain imaging on MRI or CT scans.  Descriptively, these lesions often were centered in white matter and gray-white junction.  Of 23 who had vascular imaging, sixteen (70%) showed abnormalities.  Larger artery disease occurred exclusively in four (13%) while mixed small and large vessel and small vessel involvement occurred in fifteen (50%) and eleven (37%).

Discussion: This case-series of VZV vasculopathy suggests that it defies some of our conventional thoughts about vasculitis.  About 30% had no pleocytosis, and 37% had no preceding rash to suggest shingles.  Also, despite our initial impression that severe disease is more common in the immunocompromised, nineteen patients had no known immune suppressing conditions.  Finally, VZV PCR has little diagnostic sensitivity, and serology remains the better diagnostic test.  I think that overall, what this series suggests is that for multi-focal strokes of uncertain etiology, VZV should always be on the differential.   

Cooling in status asthmaticus

Motivation: A case of status asthmaticus refractory to continuous nebs, steroids, theophylline, heliox, etc. Ventilation was a major issue, with severe respiratory acidosis and unacceptably high plateau pressures, despite optimization of vent settings and paralysis. This patient was cooled in an attempt to decrease the body's CO2 production, in the hope of decreasing PaCO2 and the patient's overall ventilatory requirement. Physiologically, this makes sense, but what has the literature reported about similar cases?

Literature search and results: Looking into the literature, there is a case published about treatment of severe asthma with hypothermia: Browning D, Goodrum DT. Treatment of acute severe asthma assisted by hypothermia. Anaesthesia. 1992 Mar;47(3):223-5. In this case report, a patient in refractory status asthmaticus was cooled to 30 degrees Celsius for 5 days due to rising PaCO2. While hypothermia helped with ventilatory settings, her ventilation was compromised by development of steroid-induced myopathy.

Discussion: My search for similar cases came up quite short. Hypothermia was used in our case and in this reported case in the literature was in the setting of status asthmaticus with poor/very guarded prognosis despite maximal therapy and optimal support. As predicted by physiology, cooling helped with allowing more reasonable vent parameters, but could not change the underlying process and complications related to status asthmaticus and its necessary therapies (e.g. steroid side effects, infections secondary to vent/lines/etc.). Furthermore, cooling/rewarming  is associated with its own complications. Thus, hypothermia can be seen as a temporizing agent to be considered within a plethora of medical issues in these severe cases of status asthmaticus.

Chronic Kidney Disease and Bleeding

Motivation: A man with kidney failure from polycystic kidney disease abruptly bled inside his head.  We blamed it on dysfunctional platelets and used desmopressin (DDAVP) to try to reverse his dysfunctional platelets.  Did not work, and he herniated.  Does desmopressin or other interventions really improve bleeding from dysfunctional platelets?

As way of background, chronic kidney disease increases bleeding time through dysfunction of platelet adhesion and aggregation via a variety of mechanisms including dysfunctional von Willebrand Factor (vWF), anemia, and uremic toxin accumulation.

Paper: Hedges, S.J., Dehoney, S.B., Hooper, J.S. et. al. Evidence-based treatment recommendations for uremic bleeding. Nature Clin. Prac. Neph. (2007); 3: 138-156

Methods: Systematic review of published trials.

Results: 

Cryoprecipitate: Two small controlled trials evaluated cryoprecipitate infusion to replete dysfunctional vWF.  In a prospective trial, seven patients with bleeding time > 15 minutes were infused 10 bags of cryoprecipitate resulting in decreased bleeding time in all patients after 4 hours.  In a retrospective single center analysis, 5 patients were infused with cryoprecipitate resulting in decreased bleeding time in 2 patients and no effect in three others.

Desmopressin (DDAVP): In the one randomized trial with patients on hemodialysis with bleeding time > 15 minutes, one dose of 0.4 ug/kg of DDAVP resulted in normalization of bleeding time in two of eight patients and reduction in seven of eight patients randomized to DDAVP arm.  In another prospective single center trial, one dose of 0.4 ug/kg of DDAVP resulted in normalization of bleeding time in six of twelve patients in one hour.  In two hours, 3 out of 12 had normal bleeding times.  After 24 hours, all patients reverted back to prolonged bleeding time.  Finally, in a retrospective study, one dose of 0.3 ug/kg of DDAVP resulted in normalized bleeding time in 5/12 one hour post-infusion, 2/12 four hours post-infusion, and 1/12 eight hours post-infusion.

Estrogens: Has been tested in three randomized, placebo controlled trials.  In first trial, patients received 0.6 mg/kg of IV conjugated estrogens for five days.  All patients in the estrogen treated group had normalized bleeding time within six hours.  In subsequent randomized trial, the dose used was again 0.6 mg/kg of IV conjugated estrogen for five days.  Patients receiving estrogen had significantly decreased bleeding time at days  seven and fourteen with no significant effects on day 21 and day 28.  In the final trial, patients on HD were randomized to oral conjugated estrogen (50 mg) or placebo for nine days or till normalization of bleeding time.  In the five patients randomized to estrogen, bleeding time normalized in 3 of 5 patients and decreased to less than 50% in remaining 2 patients.  The most common adverse effect was flushing.

Discussion: For the actively bleeding patient with renal failure, dysfunctional uremic platelets can be treated successfully!  In the actively bleeding patient, besides desmopressin, cryoprecipitate can also be helpful.  But, perhaps more intriguingly, conjugated estrogens may be beneficial in the short term even after six hours.  While desmopressin is presumed to induce secretion of Factor VIII from endothelial cells, the mechanism of estrogen is less clear - may work by decreasing NO production or decreasing Factor S concentrations.  I had not really considered estrogen as part of the acute therapy.  In the future, when desmopressin does not appear to stop bleeding, I will turn to cryoprecipitate and conjugated estrogens.

This was a post after a while.  Next posts will appear more frequently.