Indolent course of progressive multifocal leukoencephalopathy during natalizumab treatment in MS
Michael Y.Ko, Assistant Professor, 1653 Rush University Medical Ctr, W. Congress Parkway, Chicago, Illinois 60612michael_ko@rush.edu
Dusan Stefoski, Roumen Balabanov
Submitted May 25, 2011
Vennegoor et al. reported MRI abnormalities 4 months prior to the onset of clinical symptoms for progressive multifocal leukoencephalopathy (PML). [1] We also treated a similar natalizumab-associated PML multiple sclerosis (MS) patient with an 18-month course of progressive left lower extremity weakness before PML was confirmed.
At onset and during the subsequent 12 months, repeated brain and spine MRIs did not reveal any new or changing lesions from baseline. At one year, the MRI demonstrated a significant enlargement of a previously known right precentral gyrus demyelinating lesion. PML was suspected, but CSF JC virus (JCV) viral load—assays for 50 or greater copies—was negative. However, the suspicion of PML persisted and natalizumab was discontinued after 14 months after the onset of symptoms.
Throughout our patient’s course, the weakness progressed despite several rounds of IV corticosteroids. After 18 months, the brain MRI revealed further enlargement of the gyral lesion and two new non-enhancing lesions suggestive of PML. Repeat CSF JCV viral PCR was positive. After receiving the published empiric therapy for PML and corticosteroids for immune reconstitution inflammatory syndrome, the patient improved and later returned to work. [2]
PML can present with a protracted clinical course as seen in our patient. However, unlike Vennegoor et al.'s case, our patient had unchanged brain MRIs and a negative CSF JCV PCR even as symptoms progressed. We detected MRI abnormalities after the PML spread into the local white matter but conventional MRIs may not easily detect cortical PML lesions. [3]
Additionally, the protracted clinical course could have caused a slower rise in CSF JCV viral load, which is more difficult to detect by PCR. The sensitivity of diagnosing PML could be increased with serial PCR testing as the JCV viral load increases with disease progression. [4] Even with negative studies, PML was further suspected because IV corticosteroids did not improve the symptoms. In addition, the initial lesion enlarged.
We believe that natalizumab did not accelerate the progression of symptoms or time to confirm PML in our patient although 14 natalizumab infusions were given after symptoms appeared. Natalizumab may have initiated PML without altering its course.
References
1.Vennegoor A, Wattjes MP, van Munster ETL, et al. Indolent course of progressive multifocal leukoencephalopathy during natalizumab treatment in MS. Neurol 2011;76:574-576.
2. Clifford D, DeLuca A, Simpson DM, et al. Natalizumab-associated progressive multifocal leukoencephalopathy in patients with multiple sclerosis: lessons from 28 cases. Lancet Neurol 2010;9:438-446.
3. De Toffol B, Vidailhet M, Gray F, et al. Isolated motor control dysfunction related to progressive multifocal leukoencephalopathy during AIDS with normal MRI. Neurol 1994;44:2352-2355.
4.Landry ML, Eid T, Bannykh S, Majors E. Case report. False negative PCR despite high levels of JC virus DNA in spinal fluid: Implications on diagnostic testing. J Clin Vir 2008;43:246-249.
Disclosures: Dr. Michael Ko received consulting fees from Biogen Idec and serves on the speakers’ bureau for Biogen Idec, EMD Serono, and Pfizer.
Dr. Stefoski serves on the speakers’ bureau of and received consulting fees from Biogen Idec, Accorda, Teva Pharmaceutical and Novartis; receives royalties from Accord; listed as a co-inventor in a patent application describing the utility of cell free plasma DNA in biomarker development.
Dr. Balabanov received consulting fees from Biogen Idec, Teva Pharmaceutical, and Novartis; receives research support from the National Institute of Health and the National Multiple Sclerosis Society; is a co-inventor in a patent application describing the utility of cell free plasma DNA in biomarker development.
Vennegoor et al. reported MRI abnormalities 4 months prior to the onset of clinical symptoms for progressive multifocal leukoencephalopathy (PML). [1] We also treated a similar natalizumab-associated PML multiple sclerosis (MS) patient with an 18-month course of progressive left lower extremity weakness before PML was confirmed.
At onset and during the subsequent 12 months, repeated brain and spine MRIs did not reveal any new or changing lesions from baseline. At one year, the MRI demonstrated a significant enlargement of a previously known right precentral gyrus demyelinating lesion. PML was suspected, but CSF JC virus (JCV) viral load—assays for 50 or greater copies—was negative. However, the suspicion of PML persisted and natalizumab was discontinued after 14 months after the onset of symptoms.
Throughout our patient’s course, the weakness progressed despite several rounds of IV corticosteroids. After 18 months, the brain MRI revealed further enlargement of the gyral lesion and two new non-enhancing lesions suggestive of PML. Repeat CSF JCV viral PCR was positive. After receiving the published empiric therapy for PML and corticosteroids for immune reconstitution inflammatory syndrome, the patient improved and later returned to work. [2] PML can present with a protracted clinical course as seen in our patient. However, unlike Vennegoor et al.'s case, our patient had unchanged brain MRIs and a negative CSF JCV PCR even as symptoms progressed. We detected MRI abnormalities after the PML spread into the local white matter but conventional MRIs may not easily detect cortical PML lesions. [3]
Additionally, the protracted clinical course could have caused a slower rise in CSF JCV viral load, which is more difficult to detect by PCR. The sensitivity of diagnosing PML could be increased with serial PCR testing as the JCV viral load increases with disease progression. [4] Even with negative studies, PML was further suspected because IV corticosteroids did not improve the symptoms. In addition, the initial lesion enlarged.
We believe that natalizumab did not accelerate the progression of symptoms or time to confirm PML in our patient although 14 natalizumab infusions were given after symptoms appeared. Natalizumab may have initiated PML without altering its course.
References
1.Vennegoor A, Wattjes MP, van Munster ETL, et al. Indolent course of progressive multifocal leukoencephalopathy during natalizumab treatment in MS. Neurol 2011;76:574-576.
2. Clifford D, DeLuca A, Simpson DM, et al. Natalizumab-associated progressive multifocal leukoencephalopathy in patients with multiple sclerosis: lessons from 28 cases. Lancet Neurol 2010;9:438-446.
3. De Toffol B, Vidailhet M, Gray F, et al. Isolated motor control dysfunction related to progressive multifocal leukoencephalopathy during AIDS with normal MRI. Neurol 1994;44:2352-2355.
4.Landry ML, Eid T, Bannykh S, Majors E. Case report. False negative PCR despite high levels of JC virus DNA in spinal fluid: Implications on diagnostic testing. J Clin Vir 2008;43:246-249.
Disclosures: Dr. Michael Ko received consulting fees from Biogen Idec and serves on the speakers’ bureau for Biogen Idec, EMD Serono, and Pfizer. Dr. Stefoski serves on the speakers’ bureau of and received consulting fees from Biogen Idec, Accorda, Teva Pharmaceutical and Novartis; receives royalties from Accord; listed as a co-inventor in a patent application describing the utility of cell free plasma DNA in biomarker development. Dr. Balabanov received consulting fees from Biogen Idec, Teva Pharmaceutical, and Novartis; receives research support from the National Institute of Health and the National Multiple Sclerosis Society; is a co-inventor in a patent application describing the utility of cell free plasma DNA in biomarker development.