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of Progressive Multifocal Leukoencephalopathy
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False negative DNA PCR test for JC Virus in Cerebrospinal Fluid Resulting in Delayed Diagnosis
of Progressive Multifocal Leukoencephalopathy
Saketh Palasamudram Shekar1*, Jeevna Kaur2 and Tanmay Parekh3
1 Department of Pulmonary and Critical care medicine, USA
2 Department of Internal Medicine, USA
3 Department of Neurology, USA
Submission: November 22, 2018; Published: January 08, 2019
*Corresponding author: Saketh Palasamudram Shekar, Department of Pulmonary and Critical care medicine, Florida, USA.
How to cite this article: Saketh P S, Jeevna K, Tanmay P. False negative DNA PCR test for JC Virus in Cerebrospinal Fluid Resulting in Delayed
Diagnosis of Progressive Multifocal Leukoencephalopathy. Open Access J Neurol Neurosurg. 2019; 9(3): 555765.
Progressive Multifocal Leukoencephalopathy is a rare disease of the Central Nervous System (CNS) caused by reactivation of the JC polyomavirus in an immunocompromised host. It carries a poor prognosis and high mortality rate. Gold standard for diagnosis is brain biopsy however the initial recommend step is to secure diagnosis with PCR showing JC virus in CSF. If negative, PCR is again repeated before attempting brain biopsy as it is the more invasive approach. There have been incidences of delayed diagnosis due to false negative CSF PCR results for JC virus. Here, we present such a case: a 73-year-old man with a recent diagnosis of Chronic Lymphocytic Leukemia on Ibrutinib therapy) who presented with worsening mentation and focal motor deficits. Work up included multiple MRI images of the brain, which demonstrated scattered foci of white matter lesions, with some lesions demonstrating hyperintense Diffusion Weighted Imaging (DWI) signal. Two lumbar punctures were performed, which were negative for infectious etiology (JC Virus negative) and yielded negative cytology. Further workup was negative for drug toxicity, infective endocarditis, primary CNS lymphoma, and primary vasculitis. Brain biopsy was ultimately performed, which demonstrated chronic active viral encephalitis, positive for SV40 by immunohistochemistry consistent with progressive multifocal leukoencephalopathy. This case highlights the importance of obtaining brain biopsy for diagnosis of PML despite negative PCR results for JC virus in CSF, if clinical suspicion remains high.
Progressive Multifocal Leukoencephalopathy (PML) is a rare demyelinating disease of the Central Nervous System (CNS) caused by JC polyomavirus (JC virus). This disease almost entirely occurs in immunocompromised patients resulting in reactivation of latent JC virus causing lytic infection of oligodendrocytes . It commonly involves the cortical white matter of the frontal and parieto-occipital lobes but can involve any part of the brain  and is associated with a high mortality rate. Median survival in non-HIV patients is three months  and therefore timely diagnosis is crucial. Current guidelines recommend diagnosis be confirmed by PCR for JC virus in Cerebrospinal Fluid (CSF), if neuroimaging is consistent with PML. Brain biopsy still remains the gold standard for diagnosis  although it is not explored enough due to invasive nature of the testing. We present a case of PML where the workup demonstrated negative PCR results for
JC virus from CSF obtained on two separate occasions, with the diagnosis ultimately being confirmed with brain biopsy.
73-year-old right handed male with medical history of Chronic Lymphocytic Leukemia (CLL) on Ibrutinib therapy daily started few months earlier. Other medical history included chronic kidney disease stage III, IgG lambda monoclonal gammopathy, bilateral hearing loss, and polymyalgia rheumatica. Patient was evaluated during a routine visit with outpatient oncology with complaints of increasing fatigue, poor appetite and episodes of incoherence. Additionally, patient felt as if his mental capabilities were diminished including decrease in activities of daily living. During this time, he also developed weakness of the left upper extremity, most noticeable in the hand. Patient, however denied headache, visual changes, abnormal speech, numbness, nausea,
vomiting or fevers.
Neurological exam was significant for inability to perform
simple tasks such as spelling ‘WORLD’ backwards and the ability
to recall three words. Motor strength was 4/5 in the upper
extremities bilaterally, and 5/5 in the lower extremities. Reflexes
were 2/4 and symmetric. Babinski was flexor bilaterally. There
was a left side pronator drift and gait exam demonstrated
unsteadiness with a stooped posture.
Initial MRI brain showed multiple scattered foci of white
matter lesions, the largest of which measured 3.5 cm involving
the right posterior frontal juxtacortical and subcortical white
matter (Figure 1). Laboratory studies revealed normal complete
blood counts with elevated sedimentation rate of 92 mm/hr.
Ibrutinib was held and patient was admitted to hospital for
further workup. Differential diagnosis based on the MRI findings
of hyperintense DWI signal changes resembling ischemic lesions
included ruling out embolic strokes in an immunocompromised
patient with possible underlying endocarditis versus a primary
CNS vasculitis. Leukemia, primary CNS lymphoma, and
underlying infectious etiology were also high on the differential
. Ultimately, work up for the above were negative. HIV testing,
Transesophageal echocardiogram were subsequently negative.
Two spinal taps were performed during the course of the work
up with initial cerebrospinal fluid analysis demonstrated WBC
count 2 cells/μl, Protein 51 mg/dl, Glucose 70 mg/dl, and RBC
2 cells/μl with negative cytology. Repeat LP performed few days
later demonstrated a WBC 4 cells/μl, Protein 55 mg/dl, Glucose
55 mg/dl, and RBC 1 cell/μl with negative cytology as well.
Both samples were sent out for EBV, CMV, Herpes simplex virus,
Enterovirus, VDRL, Lyme, Cryptococcal, VZV, and JC virus by PCR
and were reported negative.
Repeat MRI Brain revealed worsening flair signal
abnormality involving the right frontal lobe lesion measuring 3.2
x 2.8 cm which was an increase from 3.0 x 2.0 cm. The number of
scattered enhancing foci had significantly decreased compared
to prior study. Family reported that patient had started to
become frequently agitated, disoriented, and paranoid. Right
frontal lobe brain lesion biopsy was then performed which
showed chronic active viral encephalitis, positive for SV40 by
immunohistochemistry, consistent with progressive multifocal
leukoencephalopathy. Patient was started on Mefloquine 250 mg
once daily and Mirtazapine 15mg once daily, but prognosis was
PML is a rare disease known to predominantly affect
immunocompromised hosts such as those with HIV, lymphomas,
transplant recipients, and those patients on treatment with
monoclonal antibodies. It is a progressive disease with high
mortality rate and generally poor prognosis once diagnosed
. Diagnosis is usually confirmed by PCR of CSF or by CNS
tissue biopsy . Although brain biopsy is the gold standard,
guidelines typically recommend establishing diagnosis with PCR
first. If negative, physicians are recommended to repeat a spinal
tap and PCR testing. At this point, in the setting of high clinical
suspicion, a brain biopsy is warranted. Other possible etiologies,
such as lymphomas, infectious etiologies such as endocarditis,
primary CNS vasculitis, and drug toxicity must be ruled out.
There have been reports of false negative PCR results for JC
virus in the CSF, which have lead to delays in diagnosis . This
was evidenced by the case presented here. These instances could
possibly be attributed to low titers of JC virus DNA in the CSF. As
such, despite negative CSF PCR studies, a brain biopsy must be
obtained in a timely manner if there is a high clinical suspicion
for JC virus. Although overall prognosis is poor, early diagnosis
of PML can potentially improve survival in certain patients if
immunosuppression can be lifted .