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Patients with multiple sclerosis (MS) who are treated with natalizumab can have small progressive multifocal leukoencephalopathy (PML) lesions on MRI, yet have undetectable JC virus (JCV) DNA in their CSF, according to a cross-sectional, retrospective study published online ahead of print March 12 in JAMA Neurology.
The findings show that for some people with MS, PML diagnosis could be delayed if CSF sampling is negative and patients are asymptomatic, potentially resulting in worse functional outcomes and survival rates, according to Martijn T. Wijburg, MD, a neurologist at the MS Center at VU University Medical Center in Amsterdam, and colleagues.
The study also described a potential correlation between PML lesion volume and JCV copy numbers. “To our knowledge, this is the first study that shows an association between total PML lesion volume measured by brain MRI and CSF JCV polymerase chain reaction [PCR] results in patients with [natalizumab-associated PML]. This finding may have considerable implications for patient care,” said the authors.
A Retrospective Study
PML, a lytic infection of glial and neuronal cells by the JCV, can be diagnosed when a patient exhibits clinical symptoms, when JCV DNA is detected in CSF by PCR, and when specific brain lesions are seen on MRI, according to a consensus statement from the Neuroinfectious Disease section of the American Academy of Neurology.
Dr. Wijburg and his coinvestigators reviewed data from Dutch and Belgian patients considered to have natalizumab-associated PML between January 2007 and December 2014. Patients were required to meet one of the following criteria:
- Definite or probable PML, based on positive PCR and MRI findings suggestive of PML, with or without PML symptoms.
- In the absence of a positive PCR, the presence of all four of the following features: high risk of PML development, such as positive anti-JCV serostatus and natalizumab treatment duration greater than 12 months; no MS disease activity prior to PML suspicion; MRI lesions highly suggestive of PML, with lesion characteristics as previously reported and absence of lesion characteristics suggestive of other diseases, as judged by an experienced neuroradiologist; and a lesion evolution on follow-up MRI scans suggestive of PML, including development of immune reconstitution inflammatory syndrome.
In the study of 56 patients (37 women), nine patients (16.1%) had undetectable JCV DNA in CSF, and 14 (25%) were asymptomatic for PML. At the time of PML diagnosis, the median age was 45, and the median natalizumab treatment duration was 43 months. Patients with a positive PCR had larger total PML lesion volumes than did those with undetectable JCV DNA (median volume, 22.9 mL vs 6.7 mL). Logistic regression showed that a smaller PML lesion volume significantly increased the probability for undetectable JCV DNA.
The research team also observed a positive correlation between PML lesion volume and JCV copy numbers. PML lesion volume was greater in patients with PML symptoms and in patients with more widespread lesion dissemination. But no association was found between PCR results and PML lesion dissemination, signs of inflammation, or PML symptoms.
Results Suggest Need for Pharmacovigilance
The findings suggest that patients with a smaller PML lesion volume were more likely to have a negative test result for JCV, which may lead to a delayed diagnosis of PML. Patients with smaller lesion volume were also more likely to be asymptomatic, which may further delay diagnosis.
“This [finding] can result in a therapeutic dilemma. Unjustly excluding PML may have serious consequences (eg, when switching from [natalizumab] to even more potent immunosuppressive treatments, such as alemtuzumab),” said the authors.
“In patients with [natalizumab-associated PML], both the probability for a positive CSF JCV PCR result and the JCV viral load are associated with the total PML lesion volume.... As a consequence, patients with smaller PML lesion volumes are more likely to have undetectable JCV DNA, and PML can thus not reliably be excluded based on a negative PCR.”
Strict pharmacovigilance by MRI “will lead to identification of smaller [PML] lesions that associate with a higher likelihood of negative PCR results, which hampers a formal diagnosis of [PML] and may complicate patient treatment,” said the authors.
Meticulous clinical and MRI follow-up, in combination with repeated CSF JCV PCR testing, was warranted in these patients, they added. Complementary PML diagnostic approaches, such as assessing intrathecal antibody synthesis to JCV by determining the CSF JCV antibody index, may also be of additional value.
“Furthermore, undetectable JCV DNA does not completely preclude the presence of JCV DNA. Further development and improvement of ultrasensitive PCR assays may improve the diagnostic accuracy in the future.”
MRI Alone Cannot Yet Support Diagnosis
“Dr. Wijburg and colleagues raise an important point in our understanding of the development of PML by showing that small brain lesions may be present at what may be the start of JCV infection when the virus is still undetectable in CSF,” said Eugene O. Major, PhD, a consultant in the Division of Neuroimmunology and Neurovirology at NINDS in Bethesda, Maryland, in an accompanying editorial. “However, it is not yet clear how well the relationship between viral load in CSF and MRI brain lesions approximates the stages of the disease and the processes with which it affects its target brain cells.”
Repeat testing may be worthwhile when CSF testing is negative, because some patients test positive weeks after testing negative, he added. “Suspicion for PML may be increased when MRI shows signs of PML despite negative CSF testing, but it is too early to rely on MRI alone for diagnosis.”
Dr. Major has received consulting fees while serving on independent adjudication committees for Takeda/Millennium, Roche/Genentech, and GlaxoSmithKline.He has patent rights at the NIH as coinventor of the Ultrasensitive Quantitative PCR Multiplex assay for the detection of JCV DNA–distinguishing viral variants.
—Nicola Garrett
Suggested Reading
Major EO. Progressive multifocal leukoencephalopathy lesions and JC virus: the limits and value of imaging. JAMA Neurol. 2018 Mar 12 [Epub ahead of print].
Wijburg MT, Kleerekooper I, Lissenberg-Witte BI, et al. Association of progressive multifocal leukoencephalopathy lesion volume with JC virus polymerase chain reaction results in cerebrospinal fluid of natalizumab-treated patients with multiple sclerosis. JAMA Neurol. 2018 Mar 12 [Epub ahead of print].
Patients with multiple sclerosis (MS) who are treated with natalizumab can have small progressive multifocal leukoencephalopathy (PML) lesions on MRI, yet have undetectable JC virus (JCV) DNA in their CSF, according to a cross-sectional, retrospective study published online ahead of print March 12 in JAMA Neurology.
The findings show that for some people with MS, PML diagnosis could be delayed if CSF sampling is negative and patients are asymptomatic, potentially resulting in worse functional outcomes and survival rates, according to Martijn T. Wijburg, MD, a neurologist at the MS Center at VU University Medical Center in Amsterdam, and colleagues.
The study also described a potential correlation between PML lesion volume and JCV copy numbers. “To our knowledge, this is the first study that shows an association between total PML lesion volume measured by brain MRI and CSF JCV polymerase chain reaction [PCR] results in patients with [natalizumab-associated PML]. This finding may have considerable implications for patient care,” said the authors.
A Retrospective Study
PML, a lytic infection of glial and neuronal cells by the JCV, can be diagnosed when a patient exhibits clinical symptoms, when JCV DNA is detected in CSF by PCR, and when specific brain lesions are seen on MRI, according to a consensus statement from the Neuroinfectious Disease section of the American Academy of Neurology.
Dr. Wijburg and his coinvestigators reviewed data from Dutch and Belgian patients considered to have natalizumab-associated PML between January 2007 and December 2014. Patients were required to meet one of the following criteria:
- Definite or probable PML, based on positive PCR and MRI findings suggestive of PML, with or without PML symptoms.
- In the absence of a positive PCR, the presence of all four of the following features: high risk of PML development, such as positive anti-JCV serostatus and natalizumab treatment duration greater than 12 months; no MS disease activity prior to PML suspicion; MRI lesions highly suggestive of PML, with lesion characteristics as previously reported and absence of lesion characteristics suggestive of other diseases, as judged by an experienced neuroradiologist; and a lesion evolution on follow-up MRI scans suggestive of PML, including development of immune reconstitution inflammatory syndrome.
In the study of 56 patients (37 women), nine patients (16.1%) had undetectable JCV DNA in CSF, and 14 (25%) were asymptomatic for PML. At the time of PML diagnosis, the median age was 45, and the median natalizumab treatment duration was 43 months. Patients with a positive PCR had larger total PML lesion volumes than did those with undetectable JCV DNA (median volume, 22.9 mL vs 6.7 mL). Logistic regression showed that a smaller PML lesion volume significantly increased the probability for undetectable JCV DNA.
The research team also observed a positive correlation between PML lesion volume and JCV copy numbers. PML lesion volume was greater in patients with PML symptoms and in patients with more widespread lesion dissemination. But no association was found between PCR results and PML lesion dissemination, signs of inflammation, or PML symptoms.
Results Suggest Need for Pharmacovigilance
The findings suggest that patients with a smaller PML lesion volume were more likely to have a negative test result for JCV, which may lead to a delayed diagnosis of PML. Patients with smaller lesion volume were also more likely to be asymptomatic, which may further delay diagnosis.
“This [finding] can result in a therapeutic dilemma. Unjustly excluding PML may have serious consequences (eg, when switching from [natalizumab] to even more potent immunosuppressive treatments, such as alemtuzumab),” said the authors.
“In patients with [natalizumab-associated PML], both the probability for a positive CSF JCV PCR result and the JCV viral load are associated with the total PML lesion volume.... As a consequence, patients with smaller PML lesion volumes are more likely to have undetectable JCV DNA, and PML can thus not reliably be excluded based on a negative PCR.”
Strict pharmacovigilance by MRI “will lead to identification of smaller [PML] lesions that associate with a higher likelihood of negative PCR results, which hampers a formal diagnosis of [PML] and may complicate patient treatment,” said the authors.
Meticulous clinical and MRI follow-up, in combination with repeated CSF JCV PCR testing, was warranted in these patients, they added. Complementary PML diagnostic approaches, such as assessing intrathecal antibody synthesis to JCV by determining the CSF JCV antibody index, may also be of additional value.
“Furthermore, undetectable JCV DNA does not completely preclude the presence of JCV DNA. Further development and improvement of ultrasensitive PCR assays may improve the diagnostic accuracy in the future.”
MRI Alone Cannot Yet Support Diagnosis
“Dr. Wijburg and colleagues raise an important point in our understanding of the development of PML by showing that small brain lesions may be present at what may be the start of JCV infection when the virus is still undetectable in CSF,” said Eugene O. Major, PhD, a consultant in the Division of Neuroimmunology and Neurovirology at NINDS in Bethesda, Maryland, in an accompanying editorial. “However, it is not yet clear how well the relationship between viral load in CSF and MRI brain lesions approximates the stages of the disease and the processes with which it affects its target brain cells.”
Repeat testing may be worthwhile when CSF testing is negative, because some patients test positive weeks after testing negative, he added. “Suspicion for PML may be increased when MRI shows signs of PML despite negative CSF testing, but it is too early to rely on MRI alone for diagnosis.”
Dr. Major has received consulting fees while serving on independent adjudication committees for Takeda/Millennium, Roche/Genentech, and GlaxoSmithKline.He has patent rights at the NIH as coinventor of the Ultrasensitive Quantitative PCR Multiplex assay for the detection of JCV DNA–distinguishing viral variants.
—Nicola Garrett
Suggested Reading
Major EO. Progressive multifocal leukoencephalopathy lesions and JC virus: the limits and value of imaging. JAMA Neurol. 2018 Mar 12 [Epub ahead of print].
Wijburg MT, Kleerekooper I, Lissenberg-Witte BI, et al. Association of progressive multifocal leukoencephalopathy lesion volume with JC virus polymerase chain reaction results in cerebrospinal fluid of natalizumab-treated patients with multiple sclerosis. JAMA Neurol. 2018 Mar 12 [Epub ahead of print].
Patients with multiple sclerosis (MS) who are treated with natalizumab can have small progressive multifocal leukoencephalopathy (PML) lesions on MRI, yet have undetectable JC virus (JCV) DNA in their CSF, according to a cross-sectional, retrospective study published online ahead of print March 12 in JAMA Neurology.
The findings show that for some people with MS, PML diagnosis could be delayed if CSF sampling is negative and patients are asymptomatic, potentially resulting in worse functional outcomes and survival rates, according to Martijn T. Wijburg, MD, a neurologist at the MS Center at VU University Medical Center in Amsterdam, and colleagues.
The study also described a potential correlation between PML lesion volume and JCV copy numbers. “To our knowledge, this is the first study that shows an association between total PML lesion volume measured by brain MRI and CSF JCV polymerase chain reaction [PCR] results in patients with [natalizumab-associated PML]. This finding may have considerable implications for patient care,” said the authors.
A Retrospective Study
PML, a lytic infection of glial and neuronal cells by the JCV, can be diagnosed when a patient exhibits clinical symptoms, when JCV DNA is detected in CSF by PCR, and when specific brain lesions are seen on MRI, according to a consensus statement from the Neuroinfectious Disease section of the American Academy of Neurology.
Dr. Wijburg and his coinvestigators reviewed data from Dutch and Belgian patients considered to have natalizumab-associated PML between January 2007 and December 2014. Patients were required to meet one of the following criteria:
- Definite or probable PML, based on positive PCR and MRI findings suggestive of PML, with or without PML symptoms.
- In the absence of a positive PCR, the presence of all four of the following features: high risk of PML development, such as positive anti-JCV serostatus and natalizumab treatment duration greater than 12 months; no MS disease activity prior to PML suspicion; MRI lesions highly suggestive of PML, with lesion characteristics as previously reported and absence of lesion characteristics suggestive of other diseases, as judged by an experienced neuroradiologist; and a lesion evolution on follow-up MRI scans suggestive of PML, including development of immune reconstitution inflammatory syndrome.
In the study of 56 patients (37 women), nine patients (16.1%) had undetectable JCV DNA in CSF, and 14 (25%) were asymptomatic for PML. At the time of PML diagnosis, the median age was 45, and the median natalizumab treatment duration was 43 months. Patients with a positive PCR had larger total PML lesion volumes than did those with undetectable JCV DNA (median volume, 22.9 mL vs 6.7 mL). Logistic regression showed that a smaller PML lesion volume significantly increased the probability for undetectable JCV DNA.
The research team also observed a positive correlation between PML lesion volume and JCV copy numbers. PML lesion volume was greater in patients with PML symptoms and in patients with more widespread lesion dissemination. But no association was found between PCR results and PML lesion dissemination, signs of inflammation, or PML symptoms.
Results Suggest Need for Pharmacovigilance
The findings suggest that patients with a smaller PML lesion volume were more likely to have a negative test result for JCV, which may lead to a delayed diagnosis of PML. Patients with smaller lesion volume were also more likely to be asymptomatic, which may further delay diagnosis.
“This [finding] can result in a therapeutic dilemma. Unjustly excluding PML may have serious consequences (eg, when switching from [natalizumab] to even more potent immunosuppressive treatments, such as alemtuzumab),” said the authors.
“In patients with [natalizumab-associated PML], both the probability for a positive CSF JCV PCR result and the JCV viral load are associated with the total PML lesion volume.... As a consequence, patients with smaller PML lesion volumes are more likely to have undetectable JCV DNA, and PML can thus not reliably be excluded based on a negative PCR.”
Strict pharmacovigilance by MRI “will lead to identification of smaller [PML] lesions that associate with a higher likelihood of negative PCR results, which hampers a formal diagnosis of [PML] and may complicate patient treatment,” said the authors.
Meticulous clinical and MRI follow-up, in combination with repeated CSF JCV PCR testing, was warranted in these patients, they added. Complementary PML diagnostic approaches, such as assessing intrathecal antibody synthesis to JCV by determining the CSF JCV antibody index, may also be of additional value.
“Furthermore, undetectable JCV DNA does not completely preclude the presence of JCV DNA. Further development and improvement of ultrasensitive PCR assays may improve the diagnostic accuracy in the future.”
MRI Alone Cannot Yet Support Diagnosis
“Dr. Wijburg and colleagues raise an important point in our understanding of the development of PML by showing that small brain lesions may be present at what may be the start of JCV infection when the virus is still undetectable in CSF,” said Eugene O. Major, PhD, a consultant in the Division of Neuroimmunology and Neurovirology at NINDS in Bethesda, Maryland, in an accompanying editorial. “However, it is not yet clear how well the relationship between viral load in CSF and MRI brain lesions approximates the stages of the disease and the processes with which it affects its target brain cells.”
Repeat testing may be worthwhile when CSF testing is negative, because some patients test positive weeks after testing negative, he added. “Suspicion for PML may be increased when MRI shows signs of PML despite negative CSF testing, but it is too early to rely on MRI alone for diagnosis.”
Dr. Major has received consulting fees while serving on independent adjudication committees for Takeda/Millennium, Roche/Genentech, and GlaxoSmithKline.He has patent rights at the NIH as coinventor of the Ultrasensitive Quantitative PCR Multiplex assay for the detection of JCV DNA–distinguishing viral variants.
—Nicola Garrett
Suggested Reading
Major EO. Progressive multifocal leukoencephalopathy lesions and JC virus: the limits and value of imaging. JAMA Neurol. 2018 Mar 12 [Epub ahead of print].
Wijburg MT, Kleerekooper I, Lissenberg-Witte BI, et al. Association of progressive multifocal leukoencephalopathy lesion volume with JC virus polymerase chain reaction results in cerebrospinal fluid of natalizumab-treated patients with multiple sclerosis. JAMA Neurol. 2018 Mar 12 [Epub ahead of print].