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Drug-associated progressive multifocal leukoencephalopathy: a clinical, radiological, and cerebrospinal fluid analysis of 326 cases

View Article: PubMed Central - PubMed

ABSTRACT

The implementation of a variety of immunosuppressive therapies has made drug-associated progressive multifocal leukoencephalopathy (PML) an increasingly prevalent clinical entity. The purpose of this study was to investigate its diagnostic characteristics and to determine whether differences herein exist between the multiple sclerosis (MS), neoplasm, post-transplantation, and autoimmune disease subgroups. Reports of possible, probable, and definite PML according to the current diagnostic criteria were obtained by a systematic search of PubMed and the Dutch pharmacovigilance database. Demographic, epidemiologic, clinical, radiological, cerebrospinal fluid (CSF), and histopathological features were extracted from each report and differences were compared between the disease categories. In the 326 identified reports, PML onset occurred on average 29.5 months after drug introduction, varying from 14.2 to 37.8 months in the neoplasm and MS subgroups, respectively. The most common overall symptoms were motor weakness (48.6 %), cognitive deficits (43.2 %), dysarthria (26.3 %), and ataxia (24.1 %). The former two also constituted the most prevalent manifestations in each subgroup. Lesions were more often localized supratentorially (87.7 %) than infratentorially (27.4 %), especially in the frontal (64.1 %) and parietal lobes (46.6 %), and revealed enhancement in 27.6 % of cases, particularly in the MS (42.9 %) subgroup. Positive JC virus results in the first CSF sample were obtained in 63.5 %, while conversion after one or more negative outcomes occurred in 13.7 % of cases. 52.2 % of patients died, ranging from 12.0 to 83.3 % in the MS and neoplasm subgroups, respectively. In conclusion, despite the heterogeneous nature of the underlying diseases, motor weakness and cognitive changes were the two most common manifestations of drug-associated PML in all subgroups. The frontal and parietal lobes invariably constituted the predilection sites of drug-related PML lesions.

Electronic supplementary material: The online version of this article (doi:10.1007/s00415-016-8217-x) contains supplementary material, which is available to authorized users.

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Distribution of cases of drug-associated progressive multifocal leukoencephalopathy among the major disease categories (a) and subdivisions of the post-transplantation setting (b), the autoimmune diseases (c), and the neoplasms (d). Because of the large number of natalizumab-associated PML cases, multiple sclerosis was considered a distinct entity and was not included in the group of autoimmune disorders. CML chronic myeloid leukemia, CLL chronic lymphocytic leukemia, GPA granulomatosis with polyangiitis (formerly Wegener’s disease), MDS myelodysplastic syndrome, NHL non-Hodgkin lymphoma, NSCLC non-small-cell lung cancer, RA rheumatoid arthritis, SLE systematic lupus erythematosus, WM Waldenström’s macroglobulinemia
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Fig3: Distribution of cases of drug-associated progressive multifocal leukoencephalopathy among the major disease categories (a) and subdivisions of the post-transplantation setting (b), the autoimmune diseases (c), and the neoplasms (d). Because of the large number of natalizumab-associated PML cases, multiple sclerosis was considered a distinct entity and was not included in the group of autoimmune disorders. CML chronic myeloid leukemia, CLL chronic lymphocytic leukemia, GPA granulomatosis with polyangiitis (formerly Wegener’s disease), MDS myelodysplastic syndrome, NHL non-Hodgkin lymphoma, NSCLC non-small-cell lung cancer, RA rheumatoid arthritis, SLE systematic lupus erythematosus, WM Waldenström’s macroglobulinemia

Mentions: The literature search yielded 287 cases of drug-related PML in 184 case reports, 21 case series, 18 observational studies, three experimental studies, and two review articles [12–239]. Furthermore, an additional 39 reports were identified in the Dutch pharmacovigilance database, resulting in a total number of 326 documented cases. In eight cases, consensus was reached after initial doubt on the diagnosis of PML; five of them have been included, while the remaining three were finally labeled as ‘not PML’. Natalizumab, predniso(lo)ne, (dimethyl) fumarate, fludarabine, rituximab, and brentuximab vedotin were the most common single agents that have been demonstrated to trigger PML (Online Resource 1). Additionally, glucocorticoids with either azathioprine or cyclophosphamide and a regime containing four or more pharmaceuticals [usually courses of chemotherapy, frequently including rituximab (R-CHOP)] comprised the most prevalent composite culprits. The multifarious underlying diseases could be subdivided into four main categories, i.e. multiple sclerosis (MS), (other) immune-mediated disorders, neoplasms (93.8 % lymphoproliferative, 3.1 % myeloproliferative, 2.1 % solid neoplasm, 1.0 % unknown), and the post-transplantation setting (Fig. 3). Because of the relatively large number of natalizumab-associated PML cases, the former was not included in the group of immune-mediated diseases, but rather considered a distinct entity. As immunosuppressive drugs are also frequently used in the prevention of relapses in neuromyelitis optica spectrum disorder after a first episode, one might expect drug-associated PML to have been described in this patient population. However, no such reports have been identified in our search. The most common drugs associated with PML per subgroup are summarized in Online Resource 2. In general, there was considerably few drug overlap between the various disease categories, an exception being the combination of azathioprine and glucocorticoids which was used in both autoimmune disorders and the post-transplantation setting.Fig. 3


Drug-associated progressive multifocal leukoencephalopathy: a clinical, radiological, and cerebrospinal fluid analysis of 326 cases
Distribution of cases of drug-associated progressive multifocal leukoencephalopathy among the major disease categories (a) and subdivisions of the post-transplantation setting (b), the autoimmune diseases (c), and the neoplasms (d). Because of the large number of natalizumab-associated PML cases, multiple sclerosis was considered a distinct entity and was not included in the group of autoimmune disorders. CML chronic myeloid leukemia, CLL chronic lymphocytic leukemia, GPA granulomatosis with polyangiitis (formerly Wegener’s disease), MDS myelodysplastic syndrome, NHL non-Hodgkin lymphoma, NSCLC non-small-cell lung cancer, RA rheumatoid arthritis, SLE systematic lupus erythematosus, WM Waldenström’s macroglobulinemia
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC5037162&req=5

Fig3: Distribution of cases of drug-associated progressive multifocal leukoencephalopathy among the major disease categories (a) and subdivisions of the post-transplantation setting (b), the autoimmune diseases (c), and the neoplasms (d). Because of the large number of natalizumab-associated PML cases, multiple sclerosis was considered a distinct entity and was not included in the group of autoimmune disorders. CML chronic myeloid leukemia, CLL chronic lymphocytic leukemia, GPA granulomatosis with polyangiitis (formerly Wegener’s disease), MDS myelodysplastic syndrome, NHL non-Hodgkin lymphoma, NSCLC non-small-cell lung cancer, RA rheumatoid arthritis, SLE systematic lupus erythematosus, WM Waldenström’s macroglobulinemia
Mentions: The literature search yielded 287 cases of drug-related PML in 184 case reports, 21 case series, 18 observational studies, three experimental studies, and two review articles [12–239]. Furthermore, an additional 39 reports were identified in the Dutch pharmacovigilance database, resulting in a total number of 326 documented cases. In eight cases, consensus was reached after initial doubt on the diagnosis of PML; five of them have been included, while the remaining three were finally labeled as ‘not PML’. Natalizumab, predniso(lo)ne, (dimethyl) fumarate, fludarabine, rituximab, and brentuximab vedotin were the most common single agents that have been demonstrated to trigger PML (Online Resource 1). Additionally, glucocorticoids with either azathioprine or cyclophosphamide and a regime containing four or more pharmaceuticals [usually courses of chemotherapy, frequently including rituximab (R-CHOP)] comprised the most prevalent composite culprits. The multifarious underlying diseases could be subdivided into four main categories, i.e. multiple sclerosis (MS), (other) immune-mediated disorders, neoplasms (93.8 % lymphoproliferative, 3.1 % myeloproliferative, 2.1 % solid neoplasm, 1.0 % unknown), and the post-transplantation setting (Fig. 3). Because of the relatively large number of natalizumab-associated PML cases, the former was not included in the group of immune-mediated diseases, but rather considered a distinct entity. As immunosuppressive drugs are also frequently used in the prevention of relapses in neuromyelitis optica spectrum disorder after a first episode, one might expect drug-associated PML to have been described in this patient population. However, no such reports have been identified in our search. The most common drugs associated with PML per subgroup are summarized in Online Resource 2. In general, there was considerably few drug overlap between the various disease categories, an exception being the combination of azathioprine and glucocorticoids which was used in both autoimmune disorders and the post-transplantation setting.Fig. 3

View Article: PubMed Central - PubMed

ABSTRACT

The implementation of a variety of immunosuppressive therapies has made drug-associated progressive multifocal leukoencephalopathy (PML) an increasingly prevalent clinical entity. The purpose of this study was to investigate its diagnostic characteristics and to determine whether differences herein exist between the multiple sclerosis (MS), neoplasm, post-transplantation, and autoimmune disease subgroups. Reports of possible, probable, and definite PML according to the current diagnostic criteria were obtained by a systematic search of PubMed and the Dutch pharmacovigilance database. Demographic, epidemiologic, clinical, radiological, cerebrospinal fluid (CSF), and histopathological features were extracted from each report and differences were compared between the disease categories. In the 326 identified reports, PML onset occurred on average 29.5 months after drug introduction, varying from 14.2 to 37.8 months in the neoplasm and MS subgroups, respectively. The most common overall symptoms were motor weakness (48.6 %), cognitive deficits (43.2 %), dysarthria (26.3 %), and ataxia (24.1 %). The former two also constituted the most prevalent manifestations in each subgroup. Lesions were more often localized supratentorially (87.7 %) than infratentorially (27.4 %), especially in the frontal (64.1 %) and parietal lobes (46.6 %), and revealed enhancement in 27.6 % of cases, particularly in the MS (42.9 %) subgroup. Positive JC virus results in the first CSF sample were obtained in 63.5 %, while conversion after one or more negative outcomes occurred in 13.7 % of cases. 52.2 % of patients died, ranging from 12.0 to 83.3 % in the MS and neoplasm subgroups, respectively. In conclusion, despite the heterogeneous nature of the underlying diseases, motor weakness and cognitive changes were the two most common manifestations of drug-associated PML in all subgroups. The frontal and parietal lobes invariably constituted the predilection sites of drug-related PML lesions.

Electronic supplementary material: The online version of this article (doi:10.1007/s00415-016-8217-x) contains supplementary material, which is available to authorized users.

No MeSH data available.


Related in: MedlinePlus