NEW YORK (Reuters Health) – JC virus (JCV) may be undetectable in the cerebrospinal fluid (CSF) of natalizumab-treated patients with multiple sclerosis (MS) who have small progressive multifocal leukoencephalopathy (PML) lesions, according to a retrospective study.
“It is impossible to exclude PML based on a negative JCV PCR in CSF, especially in patients with low lesion volume,” Dr. Martijn T. Wijburg from VU University Medical Center in Amsterdam told Reuters Health by email.
Treatment with natalizumab can lead to PML, whose diagnosis requires the presence of clinical symptoms, MRI findings suggestive of PML and JCV DNA in CSF detected by polymerase chain reaction (PCR). However, brain MRI can reveal PML lesions months before the onset of clinical symptoms, and JCV DNA can be undetectable by PCR in CSF of patients with PML.
In their study, Dr. Wijburg from VU University Medical Center in Amsterdam and colleagues investigated the association of MRI-lesion characteristics and presence of PML symptoms with CSF JCV PCR results at the time of PML diagnosis in 56 patients with MS treated with natalizumab.
At the time of inclusion into the study, 16.1% of patients (9/56) had negative CSF JCV PCR results and 25% were asymptomatic for PML. Brain MRI detected 133 PML lesions.
Patients with positive PCR results had larger total PML lesion volume than did patients with undetectable JCV DNA, the researchers report in JAMA Neurology, online March 12.
Among PCR-positive patients, total PML lesion volume correlated directly with JCV DNA copy number.
Patients with PML symptoms had larger total PML lesion volume, compared with asymptomatic patients, and PML lesion volume increased with lesion dissemination.
There was no association between PCR results and imaging signs suggestive of inflammation or the presence of PML symptoms.
“These results support the notion that it is useless to ‘screen for’ PML using JCV PCR in CSF in patients without apparent new lesions (for instance, when switching to very strong immunosuppressants such as alemtuzumab),” Dr. Wijburg concluded. “In addition, this study provides circumstantial evidence that the JC viral load in CSF might be used as extra biomarker for disease severity, for instance, in PML treatment trials.”
The researchers note, “The intense pharmacovigilance by MRI of natalizumab-treated patients with MS leads to detection of smaller and asymptomatic lesions suggestive of PML and thus more PCR-negative CSF results, which can lead to uncertainty about the diagnosis and clinical treatment. In these patients, meticulous clinical and MRI follow-up in combination with repeated CSF JCV PCR testing is warranted.”
“Furthermore, undetectable JCV DNA does not completely preclude the presence of JCV DNA,” the team cautions. “Further development and improvement of ultrasensitive PCR assays may improve the diagnostic accuracy in the future.”
Dr. Eugene O. Major from the National Institute of Neurological Disorders and Stroke, in Bethesda, Maryland, told Reuters Health by email, “The observation that anatomical location of PML lesions does not seem to correlate with viral load in the CSF was interesting. However, we do not know from the image of a PML lesion what is the extent of viral DNA replication in an on-going infection. We do know that the higher viral load in the CSF, the more likely the progression of PML and poorer prognosis. PML is mostly multifocal; that may correlate with clinical signs, but the size of the lesion may not reflect the punch of the virus inside.”
“MR imaging plays a critical role in early suspicion for detection of PML particularly in cases where neither clinical signs nor evidence of JCV DNA in the CSF are apparent,” said Dr. Major, who wrote an editorial accompanying the study. “This observation has gained more traction in the recent past so is being incorporated into monitoring of natalizumab treated MS patients. There is a discussion of the frequency of the use of MRI particularly in patients with a high risk of PML that should lead to a uniform if not regulated consensus. In the future this may be applied to other patients at risk for PML with underlying diseases and the therapies used to treat them in addition to MS.”
“There are over 800 cases of PML in MS patients treated with natalizumab, accruing with some consistency at about 8 new cases per month,” Dr. Major added. “That should be motivation enough to find a resolution to the risk of PML that natalizumab poses for patients. Since we know the cause of PML, there should be a stronger focus on developing more tools to study and treat the actual viral agent, JCV, on its course to the infection that leads to PML.”
SOURCE: http://bit.ly/2p7lWfU and http://bit.ly/2GrlxN7
JAMA Neurol 2018.
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