Progressive multifocal leukoencephalopathy in patients with sarcoidosis Yvan Jamilloux, MD* Antoine Néel, MD* Marie Lecouffe-Desprets Anne Fèvre, MD Sebastien Kerever Benoit Guillon, MD Diane Bouvry, MD Loig Varron, MD Cécile Redares, MD Stéphane Dominique, MD Mareille Roux, MD Catherine ChapelonAbric, MD Dominique Valeyre, PhD François Ducray, PhD Claire Bernard, MD Christiane Broussolle, MD Mohamed Hamidou, PhD‡ Pascal Sève, PhD‡
ABSTRACT
Objective: To describe characteristics, risk factors, and treatment outcome of progressive multifocal leukoencephalopathy (PML) complicating sarcoidosis.
Methods: A retrospective chart and literature review was performed. Patients were identified through records from physicians of the Groupe Sarcoïdose Francophone. Each case was compared with 3 controls. Results: Ten cases were found (8 men). The median age at sarcoidosis diagnosis was 34.9 (66) years. PML and sarcoidosis were diagnosed concomitantly in 2 cases, while sarcoidosis was previously known in 8 cases, including 7 cases treated with steroids (mean time between sarcoidosis diagnosis and PML was 114 [699] months). The mean CD4 cell count was 215 (6139)/ mm3. Neurosarcoidosis was thought to be the problem in 8 cases and treatment was intensified, delaying PML diagnosis by 4.5 (63.9) months. Eight patients received PML-specific treatment. On the whole, 6 patients died of PML within a mean time of 8 (64.3) months. Patients with PML were significantly younger than controls. When combining our 10 patients with another 20 from the literature, we found that 17 patients (57%) died from sarcoidosis-associated PML; thus, the fatality rate was 57%. Conclusions: PML during sarcoidosis is often misdiagnosed. It is not associated with severe CD4 lymphocytopenia. Fatality rate is high in comparison with PML associated with other conditions. Interrupting immunosuppression remains the mainstay of treatment. Neurology® 2014;82:1307–1313 GLOSSARY JCV 5 JC virus; PML 5 progressive multifocal leukoencephalopathy.
Correspondence to Dr. Jamilloux: [email protected]
Progressive multifocal leukoencephalopathy (PML) is a rare but frequently lethal demyelinating disease due to JC virus (JCV).1 Immunosuppression has a key role in the initiation of the disease. Currently, AIDS is the leading predisposing disease but other immunocompromised states, such as sarcoidosis, have also been described.2,3 Cell-mediated immunodeficiency and chronic corticosteroid therapy are risk factors for opportunistic infections in patients with sarcoidosis.4 Christensen and Fog5 described the first association between PML and sarcoidosis in 1955. Since then, few case reports have been published. Herein, we describe a case series of sarcoidosisassociated PML. We have tried to determine the predisposing factors and assess the treatment outcomes, and have reviewed the literature. METHODS Identification of cases and controls. Cases. For this nationwide, multicenter, retrospective study, physicians from the French Study Group on Sarcoidosis were asked for known cases of sarcoidosis-associated PML. All of the patients were diagnosed as having confirmed sarcoidosis when they met the 3 criteria as presented by the American Thoracic Society/European Respiratory Society/World Association of Sarcoidosis and Other Granulomatous Disorders.6 For the diagnosis *These authors contributed equally to this work. ‡These authors contributed equally to this work. From the Service de Médecine Interne (Y.J., L.V., C. Bernard, C. Broussolle, P.S.), Hôpital de la Croix-Rousse, Lyon; Service de Médecine Interne (A.N., M.L.-D., M.H.) and Service de Neurologie (B.G.), CHU Nantes; Service d’Endocrinologie (A.F.), Diabète et Nutrition, CHU Reims; Biostatistic and Medical Information Department (S.K.), UMR 717 INSERM, Saint Louis University Hospital, AP-HP, University of Paris VII Denis Diderot, Paris; Assistance Publique–Hôpitaux de Paris (D.B., D.V.), Hôpital Avicenne et Université Paris 13, Sorbonne Paris Cité, Bobigny; Service de Médecine Interne et Gériatrie (C.R.), CH Belfort-Montbéliard, Belfort; Service de Pneumologie (S.D.), CHU Nicolle, Rouen; Service de Médecine Interne (M.R.), CH Oudot, Bourgoin-Jallieu; Department of Internal Medicine II (C.C.-A.), CHU Pitié Salpêtrière, Université Pierre et Marie Curie, Paris; and Service de Neuro-oncologie (F.D.), Hôpital Neurologique, Lyon, France. Go to Neurology.org for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article. © 2014 American Academy of Neurology
1307
25 Yes (CS)
147 CS, MTX, HCQ 900 Caucasian Mediastino-pulmonary 10 (M/35)
I
332
101
0
CS 830
CS 500
Caucasian Pulmonary 9 (F/36)
III
Caucasian Mediastino-pulmonary 1 bone marrow 8 (M/37)a
II
38
138
CS
CS, HCQ
900
720
II
II
Caucasian Mediastino-pulmonary 1 eye 1 kidney
Caucasian Mediastino-pulmonary 1 lymphadenopathy 1 heart 1 sinus 1 eye 1 kidney 1 liver
6 (M/35)
7 (M/27)
Neurology 82
April 15, 2014
Abbreviations: CS 5 corticosteroids; CYC 5 cyclophosphamide; HCQ 5 hydroxychloroquine; INN 5 infliximab; MTX 5 methotrexate; NA 5 not available; PML 5 progressive multifocal leukoencephalopathy. a Familial history of systemic granulomatosis.
115 10 Yes (CS)
Yes (CS 1 CYC)
NA
NA
15 Yes (CS)
No
NA
No
Yes (CS 1 MTX 1 CYC)
131 60 Yes (CS) 67 CS, MTX, HCQ — IV Caucasian Mediastino-pulmonary 5 (M/42)
Yes (CS 1 HCQ) 25
Yes (CS) 426 No
No
Yes (CS) 354
No
0
171
No 1,530
1,620
II
II
Caucasian Mediastino-pulmonary
Caucasian Mediastino-pulmonary
3 (M/41)
4 (F/32)
Yes (CS)
Yes (CS 1 INN) NA 10 Yes (CS 1 INN) 96 CS, MTX, CYC, INN 1,299 II African 2 (M/24)
Mediastino-pulmonary 1 possible neurosarcoidosis 1 eye
Yes (CS 1 CYC)
Yes (CS) 167 No 146 CS 300 II Caucasian Mediastino-pulmonary 1 (M/40)
Localization of sarcoidosis Ethnicity
No
Misdiagnosis (treatment for neurosarcoidosis) CD4 count, /mm3 CS dosage, mg/d Sarcoidosis treatment at PML onset Time to first neurologic symptoms, mo Previous sarcoidosis treatment Lymphocyte Stage rate, /mm3 Case (sex/ age, y)
Characteristics of 10 patients with sarcoidosis-associated PML Table 1 1308
of PML, we applied different levels of certainty according to the recently published diagnostic criteria.7 Granular neuronopathy due to JCV infection and BK virus infection were excluded, and patients positive for HIV infection were excluded as well. Controls. Each case was compared with 3 controls who had sarcoidosis without PML. Controls were randomly selected among records of 298 incident cases of confirmed sarcoidosis seen at our tertiary internal medicine unit, between 2002 and 2006.
Data collection. Using a comprehensive questionnaire, medical records were assessed for demographic, clinical, imaging, and laboratory features. Neurosarcoidosis was diagnosed according to the criteria of Zajicek et al.8 For PML, data collection included time to first neurologic symptoms since sarcoidosis diagnosis, presenting symptoms, time from first symptom to PML diagnosis, clinical and paraclinical findings, PML diagnosis methods, misdiagnosis and delay to correct diagnosis, attempted treatment, outcome, survival time, and cause of death. Data retrieval was completed by June 2013 and patients still alive were censored on the date of their last clinical visit. Literature review. We conducted a computer-assisted (PubMed, National Library of Medicine, Bethesda, MD) search of publications in English and French from 1971 through June 2013 (keywords: progressive multifocal leukoencephalopathy, JC virus, sarcoidosis). Only cases with well-documented clinical summaries and relevant information were included. Statistical analysis. Categorical variables (percentages) were compared using Fisher exact or x2 tests and continuous variables (means 6 SD) were compared using unpaired t or MannWhitney tests. The influence of treatment effects on survival were estimated by the Kaplan-Meier method and compared by the log-rank test, with hazard ratio estimated by the Cox model. All tests were 2-tailed, and statistical significance was set at the p , 0.05 level. All analyses were performed using R software version 2.15 (R Foundation for Statistical Computing, Vienna, Austria). Ethics. Because of the retrospective nature of the study, it was exempted from the University of Lyon Institutional Review Board approval. The authors have read the Helsinki Declaration and have followed the guidelines in this study. RESULTS Ten cases were identified from 7 centers in France. Two cases have been reported previously in part.9,10
Sarcoidosis. Demography and presenting symptoms. Patient characteristics are summarized in table 1. The median age at sarcoidosis onset was 34.9 (66) years. None had medical history of opportunistic infection, autoimmune disease, malignancy, or transplantation. All of the patients had histologic demonstration of noncaseating granulomas. The median lymphocyte rate was 955 (6448)/mm3. Treatment and outcome. Corticosteroids were introduced at presentation in 4 patients and secondarily in 4 other patients. Two patients never received any treatment. The mean duration and dosage of steroids at this time were 58 (622) months and 24 (619) mg/d of prednisone equivalent. The mean time between sarcoidosis diagnosis and the occurrence of neurologic symptoms was 114
(699) months. Mean age at PML onset was 44 (69) years. In 2 patients, sarcoidosis was discovered at the time of PML diagnosis. The mean CD4 cell count at this time was 215 (6139)/mm3. A diagnosis of neurosarcoidosis was initially suspected in 8 cases and led to starting or increasing corticosteroids. Infliximab was maintained in one patient. Three patients also received cyclophosphamide infusions. The mean delay to diagnosis correction was 4.5 (63.9) months. All misdiagnosed cases experienced a worsening of their neurologic symptoms during this delay. JCV-related PML. Signs and symptoms. Presenting symptoms of PML are detailed in table 2. All patients had at least one lumbar puncture: 2 had CSF pleocytosis, and 2 had an elevated CSF immunoglobulin G synthesis rate. Imaging findings. On MRI, lesions were bilateral (n 5 10), asymmetrical (n 5 9), with low signal intensity on T1-weighted images (n 5 10), and with high signal intensity on T2-weighted and fluidattenuated inversion recovery images (n 5 9), and there was no contrast enhancement after gadolinium administration in most cases (n 5 7). Lesions were found in the subcortical white matter (n 5 7), in the cerebellum (n 5 4), in the corpus callosum (n 5 2), and/or in the basal ganglia (n 5 2). Diagnosis confirmation. All patients had definite PML. The mean time from neurologic symptom
Table 2
Case (sex/ age, y)
onset to PML diagnosis was 3.6 (62.9) months. Histologic analyses of brain biopsies revealed demyelinating lesions (n 5 4), enlarged oligodendrocytes (n 5 4), bizarre astrocytes (n 5 5), inflammatory infiltrates (n 5 4), and foamy macrophages (n 5 1). When it was done, JCV PCR on brain tissue was positive in 3 of 3 patients, in situ hybridization was positive in 2 of 2 patients, and immunohistochemistry was positive in 2 of 2 patients. PML treatment and outcome. Eight patients received a specific treatment for PML. Patient 2 did not and recovered spontaneously. Patient 4 was treated only with corticosteroids; he experienced clinical worsening until coma and died within 5 months after PML onset. When reported, the treatment tolerance was good, except for interleukin-2, which was associated with cutaneous rash and fever. Overall, 6 patients died within 8 (64.3) months after the symptom onset and within 3.7 (62.1) months after PML diagnosis. The cause of death was PML in all the cases. Comparison of cases vs controls. The characteristics of
cases and controls are shown in table 3. The only significant difference was a younger age in the patients with PML. Mean lymphocyte rate was lower in the case group but the difference was not significant. Literature review. Twenty additional cases were identi-
fied (table 4).11–30
Features, treatments, and outcomes of 10 patients with sarcoidosis-associated PML
Clinical manifestations
Time from first symptom to diagnosis, mo
Abnormal brain MRI
Method of diagnosis
Treatment
Tolerance
Outcome
Last clinical contact, mo
1 (M/53)
Left hemiparesis, ataxia, disorder of consciousness, psychiatric manifestations
4
Yes
CSF PCR, brain biopsy
Cidofovir, mirtazapine
Good
Clinical and MRI improvement
2 (M/32)
Cognitive impairment, ataxia, seizures, headaches
4
Yes
Brain biopsy
No
—
Spontaneous 80 clinical and imaging improvement
3 (M/41)
Ataxia, binocular diplopia
1
Yes
Brain biopsy
Cytarabine, mirtazapine
Good
Clinical and MRI improvement
53
4 (F/46)
Right hemiparesis, aphasia, ataxia, disorder of consciousness, psychiatric manifestations, hemianopsia, headaches
1
Yes
Brain biopsy
No
—
Death
5
5 (M/47)
Right hemiparesis, cognitive 2 impairment, disorder of consciousness, psychiatric manifestations
Yes
Brain biopsy
Cidofovir, IL-2
Death Fever, rash, and neurologic worsening with IL-2
4
6 (M/38)
Right hemiparesis, aphasia, cognitive impairment
1
Yes
CSF PCR
Cidofovir, mirtazapine
Good
Clinical and MRI stabilization
20
7 (M/38)
Ataxia, headaches
9
Yes
CSF PCR
Mefloquine
NA
Death
10
8 (M/37)
Right hemiparesis, aphasia
8
Yes
CSF PCR, brain biopsy
IL-2
Nonpruriginous rash
Death
15
9 (F/63)
Alexia, cognitive impairment 4
Yes
CSF PCR
Cidofovir
Good
Death
11
10 (M/47)
Cognitive impairment
Yes
Brain biopsy
Cidofovir, IL-2
NA
Death
5
2
10
Abbreviations: IL-2 5 interleukin-2; NA 5 not available; PML 5 progressive multifocal leukoencephalopathy. Neurology 82
April 15, 2014
1309
Table 3
Comparison of patients with sarcoidosis-associated PML and controls Cases (n 5 10)
Controls (n 5 30)
p Value
35 (24–42)
48 (18–78)
0.002a
M
8 (80)
16 (53)
F
2 (20)
14 (47)
Mean age, y (range) Sex
0.26
Ethnicity
0.40
Caucasian
9 (90)
22 (73)
Non-Caucasian
1 (10)
8 (27)
No. of comorbidities
0.99
0
6 (60)
15 (50)
1
2 (20)
8 (27)
‡2
2 (20)
7 (23)
Extrathoracic involvement
4 (40)
18 (60)
0.30
Dyspnea
5 (50)
9 (30)
0.28
Pulmonary function tests Obstructive lung disease
2 (25)
10 (42)
0.48
Restrictive lung disease
3 (38)
7 (29)
0.68
1 (13)
2 (10)
—
Decreased CO diffusion Mean lymphocyte rate, /mm
955
1,258
0.13
Lymphocytes
ABSTRACT
Objective: To describe characteristics, risk factors, and treatment outcome of progressive multifocal leukoencephalopathy (PML) complicating sarcoidosis.
Methods: A retrospective chart and literature review was performed. Patients were identified through records from physicians of the Groupe Sarcoïdose Francophone. Each case was compared with 3 controls. Results: Ten cases were found (8 men). The median age at sarcoidosis diagnosis was 34.9 (66) years. PML and sarcoidosis were diagnosed concomitantly in 2 cases, while sarcoidosis was previously known in 8 cases, including 7 cases treated with steroids (mean time between sarcoidosis diagnosis and PML was 114 [699] months). The mean CD4 cell count was 215 (6139)/ mm3. Neurosarcoidosis was thought to be the problem in 8 cases and treatment was intensified, delaying PML diagnosis by 4.5 (63.9) months. Eight patients received PML-specific treatment. On the whole, 6 patients died of PML within a mean time of 8 (64.3) months. Patients with PML were significantly younger than controls. When combining our 10 patients with another 20 from the literature, we found that 17 patients (57%) died from sarcoidosis-associated PML; thus, the fatality rate was 57%. Conclusions: PML during sarcoidosis is often misdiagnosed. It is not associated with severe CD4 lymphocytopenia. Fatality rate is high in comparison with PML associated with other conditions. Interrupting immunosuppression remains the mainstay of treatment. Neurology® 2014;82:1307–1313 GLOSSARY JCV 5 JC virus; PML 5 progressive multifocal leukoencephalopathy.
Correspondence to Dr. Jamilloux: [email protected]
Progressive multifocal leukoencephalopathy (PML) is a rare but frequently lethal demyelinating disease due to JC virus (JCV).1 Immunosuppression has a key role in the initiation of the disease. Currently, AIDS is the leading predisposing disease but other immunocompromised states, such as sarcoidosis, have also been described.2,3 Cell-mediated immunodeficiency and chronic corticosteroid therapy are risk factors for opportunistic infections in patients with sarcoidosis.4 Christensen and Fog5 described the first association between PML and sarcoidosis in 1955. Since then, few case reports have been published. Herein, we describe a case series of sarcoidosisassociated PML. We have tried to determine the predisposing factors and assess the treatment outcomes, and have reviewed the literature. METHODS Identification of cases and controls. Cases. For this nationwide, multicenter, retrospective study, physicians from the French Study Group on Sarcoidosis were asked for known cases of sarcoidosis-associated PML. All of the patients were diagnosed as having confirmed sarcoidosis when they met the 3 criteria as presented by the American Thoracic Society/European Respiratory Society/World Association of Sarcoidosis and Other Granulomatous Disorders.6 For the diagnosis *These authors contributed equally to this work. ‡These authors contributed equally to this work. From the Service de Médecine Interne (Y.J., L.V., C. Bernard, C. Broussolle, P.S.), Hôpital de la Croix-Rousse, Lyon; Service de Médecine Interne (A.N., M.L.-D., M.H.) and Service de Neurologie (B.G.), CHU Nantes; Service d’Endocrinologie (A.F.), Diabète et Nutrition, CHU Reims; Biostatistic and Medical Information Department (S.K.), UMR 717 INSERM, Saint Louis University Hospital, AP-HP, University of Paris VII Denis Diderot, Paris; Assistance Publique–Hôpitaux de Paris (D.B., D.V.), Hôpital Avicenne et Université Paris 13, Sorbonne Paris Cité, Bobigny; Service de Médecine Interne et Gériatrie (C.R.), CH Belfort-Montbéliard, Belfort; Service de Pneumologie (S.D.), CHU Nicolle, Rouen; Service de Médecine Interne (M.R.), CH Oudot, Bourgoin-Jallieu; Department of Internal Medicine II (C.C.-A.), CHU Pitié Salpêtrière, Université Pierre et Marie Curie, Paris; and Service de Neuro-oncologie (F.D.), Hôpital Neurologique, Lyon, France. Go to Neurology.org for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article. © 2014 American Academy of Neurology
1307
25 Yes (CS)
147 CS, MTX, HCQ 900 Caucasian Mediastino-pulmonary 10 (M/35)
I
332
101
0
CS 830
CS 500
Caucasian Pulmonary 9 (F/36)
III
Caucasian Mediastino-pulmonary 1 bone marrow 8 (M/37)a
II
38
138
CS
CS, HCQ
900
720
II
II
Caucasian Mediastino-pulmonary 1 eye 1 kidney
Caucasian Mediastino-pulmonary 1 lymphadenopathy 1 heart 1 sinus 1 eye 1 kidney 1 liver
6 (M/35)
7 (M/27)
Neurology 82
April 15, 2014
Abbreviations: CS 5 corticosteroids; CYC 5 cyclophosphamide; HCQ 5 hydroxychloroquine; INN 5 infliximab; MTX 5 methotrexate; NA 5 not available; PML 5 progressive multifocal leukoencephalopathy. a Familial history of systemic granulomatosis.
115 10 Yes (CS)
Yes (CS 1 CYC)
NA
NA
15 Yes (CS)
No
NA
No
Yes (CS 1 MTX 1 CYC)
131 60 Yes (CS) 67 CS, MTX, HCQ — IV Caucasian Mediastino-pulmonary 5 (M/42)
Yes (CS 1 HCQ) 25
Yes (CS) 426 No
No
Yes (CS) 354
No
0
171
No 1,530
1,620
II
II
Caucasian Mediastino-pulmonary
Caucasian Mediastino-pulmonary
3 (M/41)
4 (F/32)
Yes (CS)
Yes (CS 1 INN) NA 10 Yes (CS 1 INN) 96 CS, MTX, CYC, INN 1,299 II African 2 (M/24)
Mediastino-pulmonary 1 possible neurosarcoidosis 1 eye
Yes (CS 1 CYC)
Yes (CS) 167 No 146 CS 300 II Caucasian Mediastino-pulmonary 1 (M/40)
Localization of sarcoidosis Ethnicity
No
Misdiagnosis (treatment for neurosarcoidosis) CD4 count, /mm3 CS dosage, mg/d Sarcoidosis treatment at PML onset Time to first neurologic symptoms, mo Previous sarcoidosis treatment Lymphocyte Stage rate, /mm3 Case (sex/ age, y)
Characteristics of 10 patients with sarcoidosis-associated PML Table 1 1308
of PML, we applied different levels of certainty according to the recently published diagnostic criteria.7 Granular neuronopathy due to JCV infection and BK virus infection were excluded, and patients positive for HIV infection were excluded as well. Controls. Each case was compared with 3 controls who had sarcoidosis without PML. Controls were randomly selected among records of 298 incident cases of confirmed sarcoidosis seen at our tertiary internal medicine unit, between 2002 and 2006.
Data collection. Using a comprehensive questionnaire, medical records were assessed for demographic, clinical, imaging, and laboratory features. Neurosarcoidosis was diagnosed according to the criteria of Zajicek et al.8 For PML, data collection included time to first neurologic symptoms since sarcoidosis diagnosis, presenting symptoms, time from first symptom to PML diagnosis, clinical and paraclinical findings, PML diagnosis methods, misdiagnosis and delay to correct diagnosis, attempted treatment, outcome, survival time, and cause of death. Data retrieval was completed by June 2013 and patients still alive were censored on the date of their last clinical visit. Literature review. We conducted a computer-assisted (PubMed, National Library of Medicine, Bethesda, MD) search of publications in English and French from 1971 through June 2013 (keywords: progressive multifocal leukoencephalopathy, JC virus, sarcoidosis). Only cases with well-documented clinical summaries and relevant information were included. Statistical analysis. Categorical variables (percentages) were compared using Fisher exact or x2 tests and continuous variables (means 6 SD) were compared using unpaired t or MannWhitney tests. The influence of treatment effects on survival were estimated by the Kaplan-Meier method and compared by the log-rank test, with hazard ratio estimated by the Cox model. All tests were 2-tailed, and statistical significance was set at the p , 0.05 level. All analyses were performed using R software version 2.15 (R Foundation for Statistical Computing, Vienna, Austria). Ethics. Because of the retrospective nature of the study, it was exempted from the University of Lyon Institutional Review Board approval. The authors have read the Helsinki Declaration and have followed the guidelines in this study. RESULTS Ten cases were identified from 7 centers in France. Two cases have been reported previously in part.9,10
Sarcoidosis. Demography and presenting symptoms. Patient characteristics are summarized in table 1. The median age at sarcoidosis onset was 34.9 (66) years. None had medical history of opportunistic infection, autoimmune disease, malignancy, or transplantation. All of the patients had histologic demonstration of noncaseating granulomas. The median lymphocyte rate was 955 (6448)/mm3. Treatment and outcome. Corticosteroids were introduced at presentation in 4 patients and secondarily in 4 other patients. Two patients never received any treatment. The mean duration and dosage of steroids at this time were 58 (622) months and 24 (619) mg/d of prednisone equivalent. The mean time between sarcoidosis diagnosis and the occurrence of neurologic symptoms was 114
(699) months. Mean age at PML onset was 44 (69) years. In 2 patients, sarcoidosis was discovered at the time of PML diagnosis. The mean CD4 cell count at this time was 215 (6139)/mm3. A diagnosis of neurosarcoidosis was initially suspected in 8 cases and led to starting or increasing corticosteroids. Infliximab was maintained in one patient. Three patients also received cyclophosphamide infusions. The mean delay to diagnosis correction was 4.5 (63.9) months. All misdiagnosed cases experienced a worsening of their neurologic symptoms during this delay. JCV-related PML. Signs and symptoms. Presenting symptoms of PML are detailed in table 2. All patients had at least one lumbar puncture: 2 had CSF pleocytosis, and 2 had an elevated CSF immunoglobulin G synthesis rate. Imaging findings. On MRI, lesions were bilateral (n 5 10), asymmetrical (n 5 9), with low signal intensity on T1-weighted images (n 5 10), and with high signal intensity on T2-weighted and fluidattenuated inversion recovery images (n 5 9), and there was no contrast enhancement after gadolinium administration in most cases (n 5 7). Lesions were found in the subcortical white matter (n 5 7), in the cerebellum (n 5 4), in the corpus callosum (n 5 2), and/or in the basal ganglia (n 5 2). Diagnosis confirmation. All patients had definite PML. The mean time from neurologic symptom
Table 2
Case (sex/ age, y)
onset to PML diagnosis was 3.6 (62.9) months. Histologic analyses of brain biopsies revealed demyelinating lesions (n 5 4), enlarged oligodendrocytes (n 5 4), bizarre astrocytes (n 5 5), inflammatory infiltrates (n 5 4), and foamy macrophages (n 5 1). When it was done, JCV PCR on brain tissue was positive in 3 of 3 patients, in situ hybridization was positive in 2 of 2 patients, and immunohistochemistry was positive in 2 of 2 patients. PML treatment and outcome. Eight patients received a specific treatment for PML. Patient 2 did not and recovered spontaneously. Patient 4 was treated only with corticosteroids; he experienced clinical worsening until coma and died within 5 months after PML onset. When reported, the treatment tolerance was good, except for interleukin-2, which was associated with cutaneous rash and fever. Overall, 6 patients died within 8 (64.3) months after the symptom onset and within 3.7 (62.1) months after PML diagnosis. The cause of death was PML in all the cases. Comparison of cases vs controls. The characteristics of
cases and controls are shown in table 3. The only significant difference was a younger age in the patients with PML. Mean lymphocyte rate was lower in the case group but the difference was not significant. Literature review. Twenty additional cases were identi-
fied (table 4).11–30
Features, treatments, and outcomes of 10 patients with sarcoidosis-associated PML
Clinical manifestations
Time from first symptom to diagnosis, mo
Abnormal brain MRI
Method of diagnosis
Treatment
Tolerance
Outcome
Last clinical contact, mo
1 (M/53)
Left hemiparesis, ataxia, disorder of consciousness, psychiatric manifestations
4
Yes
CSF PCR, brain biopsy
Cidofovir, mirtazapine
Good
Clinical and MRI improvement
2 (M/32)
Cognitive impairment, ataxia, seizures, headaches
4
Yes
Brain biopsy
No
—
Spontaneous 80 clinical and imaging improvement
3 (M/41)
Ataxia, binocular diplopia
1
Yes
Brain biopsy
Cytarabine, mirtazapine
Good
Clinical and MRI improvement
53
4 (F/46)
Right hemiparesis, aphasia, ataxia, disorder of consciousness, psychiatric manifestations, hemianopsia, headaches
1
Yes
Brain biopsy
No
—
Death
5
5 (M/47)
Right hemiparesis, cognitive 2 impairment, disorder of consciousness, psychiatric manifestations
Yes
Brain biopsy
Cidofovir, IL-2
Death Fever, rash, and neurologic worsening with IL-2
4
6 (M/38)
Right hemiparesis, aphasia, cognitive impairment
1
Yes
CSF PCR
Cidofovir, mirtazapine
Good
Clinical and MRI stabilization
20
7 (M/38)
Ataxia, headaches
9
Yes
CSF PCR
Mefloquine
NA
Death
10
8 (M/37)
Right hemiparesis, aphasia
8
Yes
CSF PCR, brain biopsy
IL-2
Nonpruriginous rash
Death
15
9 (F/63)
Alexia, cognitive impairment 4
Yes
CSF PCR
Cidofovir
Good
Death
11
10 (M/47)
Cognitive impairment
Yes
Brain biopsy
Cidofovir, IL-2
NA
Death
5
2
10
Abbreviations: IL-2 5 interleukin-2; NA 5 not available; PML 5 progressive multifocal leukoencephalopathy. Neurology 82
April 15, 2014
1309
Table 3
Comparison of patients with sarcoidosis-associated PML and controls Cases (n 5 10)
Controls (n 5 30)
p Value
35 (24–42)
48 (18–78)
0.002a
M
8 (80)
16 (53)
F
2 (20)
14 (47)
Mean age, y (range) Sex
0.26
Ethnicity
0.40
Caucasian
9 (90)
22 (73)
Non-Caucasian
1 (10)
8 (27)
No. of comorbidities
0.99
0
6 (60)
15 (50)
1
2 (20)
8 (27)
‡2
2 (20)
7 (23)
Extrathoracic involvement
4 (40)
18 (60)
0.30
Dyspnea
5 (50)
9 (30)
0.28
Pulmonary function tests Obstructive lung disease
2 (25)
10 (42)
0.48
Restrictive lung disease
3 (38)
7 (29)
0.68
1 (13)
2 (10)
—
Decreased CO diffusion Mean lymphocyte rate, /mm
955
1,258
0.13
Lymphocytes
