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Methods: Review of thirty patients (previous published cases and unpublished cases) with serologic or PCR proof of positive VZV and neurologic signs or symptoms attributed to VZV infection by the reviewing authors.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