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Robert C. Griggs, MD

Editors’ Note: In response to the article “Progressive multifocal leukoencephalopathy in patients with sarcoidosis,” Drs. Lefaucheur et al. report a patient with sarcoidosis developing possible progressive multifocal leukoencephalopathy despite 4 negative JC virus CSF PCRs and being treated with mirtazapine and IV immunoglobulin. Authors Jamilloux et al. comment on the case. In reference to “Contribution of Alzheimer disease to mortality in the United States,” Dr. Campbell-Taylor calls attention to the confusion surrounding the completion and interpretation of death certificates. Authors James et al. clarify their methodology and make the insightful point that pinpointing a single cause of death may not accurately characterize the process of dying for many older people. —Megan Alcauskas, MD, and Robert C. Griggs, MD


Romain Lefaucheur, Patrick Ahtoy, Jean Paul Bouwyn, David Maltête, Bertrand Bourre, Rouen, France: We read the article by Jamilloux et al.1 with interest. As demonstrated, progressive multifocal leukoencephalopathy (PML) in sarcoidosis is a disease with poor prognosis and there is no guideline for treatment. We report a 30-year-old patient who presented with progressive aphasia, right hemiparesis, and headaches. His medical history included a pulmonary sarcoidosis diagnosed on mediastinal node biopsy 5 years earlier and treated with low doses of corticosteroids (30 mg/d). Brain MRI disclosed large asymmetrical white matter hyperintensities on fluid-attenuated inversion recovery sequences without gadolinium enhancement. CSF examination showed neither pleocytosis nor elevated protein level. JC virus (JCV) PCR in CSF was negative and remained negative for the 3 other consecutive CSF examinations. Further investigation excluded BK virus, varicella-zoster virus, HIV infection, and other causes of encephalopathy. We hypothesized that the patient had possible PML.2 Corticosteroids were stopped and mirtazapine (45 mg per day) and mefloquine (250 mg weekly) were introduced. Mefloquine was quickly stopped because the patient presented bilateral optic neuritis. As the patient had hypogammaglobulinemia (6.88 g/L), we decided to introduce IV immunoglobulins

(IVIg) (25 g/mo). The patient progressively improved and only a discrete aphasia persisted. He is stable at 54 months of follow-up. Sarcoidosis-associated PML cannot be attributed to CD4 lymphocytopenia only, suggesting more complex underlying mechanisms. Our observation emphasizes that IVIg can be considered in sarcoidosis-associated PML treatment. Author Response: Yvan Jamilloux, Lyon; Antoine Néel, Nantes; Christiane Broussolle, Lyon; Mohamed Hamidou, Nantes; Pascal Seve, Lyon, France: We thank Lefaucheur et al. for their observations regarding our study on PML complicating sarcoidosis.1 Although not stated, none of our patients had hypogammaglobulinemia. In about 10% of cases, common variable immunodeficiency (CVID) manifests as granulomatous disease and cases of JCV infection have been reported.3,4 When considering the association of granulomas and PML, CVID must be considered as a differential diagnosis. In the case reported by Lefaucheur et al., hypogammaglobulinemia is probably due to high (30 mg/d is not low) steroid uptake and the results of electrophoresis when sarcoidosis was diagnosed is helpful. In this observation, the PCR for JCV in the CSF remained negative despite 4 repetitions. The lack of identification of JCV DNA led to the diagnosis of possible PML, according to recent criteria.5 However, this demonstrates that this test can be negative (38% of the reported cases), at least during early phases, and does not rule out the diagnosis of PML. The use of IVIg in sarcoidosis-associated PML has never been reported. Contrary to the cellular immune response, which plays a vital role in controlling the virus, the humoral immune response has not been shown to control JCV infection. The virus seems to have adapted to replicate and disseminate, possibly through B cells and their progenitors. Moreover, despite being present in 60%–80% of adults, antibodies to JCV do not confer protection against JCV.6 Thus, IVIg are unlikely to be effective against JCV. Exceptional cases of spontaneous improvement of PML have been reported7 but, in the discussed case, the positive outcome could merely result from the discontinuation of steroid therapy. The off-label use of mirtazapine in PML has had mixed results.8 This treatment is given on the basis of in vitro data. Prospective studies are necessary to identify effective drugs. Neurology 83

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Jamilloux Y, Néel A, Lecouffe-Desprets M, et al. Progressive multifocal leukoencephalopathy in patients with sarcoidosis. Neurology 2014;82:1307–1313. Berger JR, Aksamit AJ, Clifford DB, et al. PML diagnostic criteria: consensus statement from the AAN neuroinfectious disease section. Neurology 2013;80:1430–1438. Pavic M, Pasquet F, Fieschi C, Malphettes M, Sève P. Granulomatosis and primary immunodeficiency in adulthood [in French]. Rev Med Interne 2013;34:154–158. Resnick ES, Moshier EL, Godbold JH, CunninghamRundles C. Morbidity and mortality in common variable immune deficiency over 4 decades. Blood 2012;119: 1650–1657. Berger JR, Aksamit AJ, Clifford DB, et al. PML diagnostic criteria: consensus statement from the AAN neuroinfectious disease section. Neurology 2013;80:1430–1438. Weber F, Goldmann C, Krämer M, et al. Cellular and humoral immune response in progressive multifocal leukoencephalopathy. Ann Neurol 2001;49:636–642. Rueger MA, Miletic H, Dorries K, et al. Long-term remission in progressive multifocal leukoencephalopathy caused by idiopathic CD41 T lymphocytopenia: a case report. Clin Infect Dis 2006;42:e53–e56. Marzocchetti A, Tompkins T, Clifford DB, et al. Determinants of survival in progressive multifocal leukoencephalopathy. Neurology 2009;73:1551–1558.


Irene Campbell-Taylor, New Waterford, Canada: I read the article by James et al.1 and would like to comment on some of the authors’ confusing statements. The authors stated: “Death certificates often list the immediate cause of death, such as pneumonia, rather than listing dementia as an underlying cause.” It is not an “instead of” issue. Immediate cause and underlying cause are 2 different things. Immediate cause is usually something like pneumonia, the event that caused the heart and lungs to stop. This is the reason that physicians are instructed never to put “cardiopulmonary arrest” as the immediate cause as everybody dies of cardiopulmonary arrest. Under that line on the certificate are 2 words “due to” in small print and this is where the underlying, actual cause of death is listed. However, the misdiagnosis rate for Alzheimer disease (AD) is at least 50%, so the cause of death as AD is also possibly incorrect. The authors

contend that AD was confirmed through autopsy for about 90% of those who were clinically diagnosed. That is 90% of 21% of the total. It was not—probably could not have been—verified in the total. The article is based on the inability of physicians to accurately complete certificates of death, thereby causing serious doubt as to the actual numbers of persons whose cause of death is anything because the underlying and antecedent cause is not given. A valid certificate might read pneumonia due to congestive heart failure due to chronic obstructive pulmonary disease (COPD). Cause of death: COPD. Apparently, we should be spending more time teaching physicians how to fill in death certificates to obtain valid numbers. This is a confusing and confused article. Author Response: Bryan James, Sue Leurgans, David Bennett, Chicago: We appreciate Dr. Campbell-Taylor’s feedback and regret any confusion. We appreciate the distinction between “immediate” and “underlying” causes of death, and it is up to the Centers for Disease Control and Prevention to decide how US death certificates should be completed. Our goal was to estimate excess deaths due to AD regardless of the immediate or secondary causes of death. Therefore, we prospectively followed older persons without dementia, and accurately counted who developed AD and the excess deaths associated with having AD. This approach is agnostic to the exact series of events that lead to death. It strongly implicates AD as an underlying cause in many more deaths than reported. Our crude estimate of 500,0001 excess deaths in the United States is likely valid, although it will be important to see results from other cohort studies. We introduced the concept of mixed mortality to reflect how many chronic conditions contribute to death in old age. Trying to identify a single cause of death may not accurately reflect the process of dying for most older persons. Overall, our study suggests that developing AD markedly increases one’s risk of death and contributes to more than half a million deaths in the United States each year. © 2014 American Academy of Neurology 1.

James BD, Leurgans SE, Hebert LE, Scherr PA, Yaffe K, Bennett DA. Contribution of Alzheimer disease to mortality in the United States. Neurology 2014;82:1045–1050.

Author disclosures are available upon request ([email protected]). 1302

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Progressive multifocal leukoencephalopathy in patients with sarcoidosis Romain Lefaucheur, Yvan Jamilloux, Patrick Ahtoy, et al. Neurology 2014;83;1301-1302 DOI 10.1212/WNL.0000000000000902 This information is current as of September 29, 2014 Updated Information & Services

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Neurology ® is the official journal of the American Academy of Neurology. Published continuously since 1951, it is now a weekly with 48 issues per year. Copyright © 2014 American Academy of Neurology. All rights reserved. Print ISSN: 0028-3878. Online ISSN: 1526-632X.

Progressive multifocal leukoencephalopathy in patients with sarcoidosis.

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