Progressive multifocal leukoencephalopathy in a non ...

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presence of PML in a non-HIV patient who was treated with monoclonal antibodies for Waldenstrom macroglobulinemia. CASE REPORT. A 71-year-old female ...
Progressive multifocal leukoencephalopathy in a non-HIV patient – A case r Szerző:Branimir Penev, Galina Kirova, Gloria Adam, Ivan Staikov www.radiologia.hu

Progressive multifocal leukoencephalopathy (PML) is a rare infection of the central nervous system, which was for the first time described in 1930. The opportunistic John Cunningham virus (JCV) causes PML in individuals with suppressed immune system and leads to changes in the brain, which can confuse the interpretation of the images. The accurate diagnosis is very important in order to ensure correct in-time treatment and cessation of disease progression (1). Herein, we highlight the presence of PML in a non-HIV patient who was treated with monoclonal antibodies for Waldenstrom macroglobulinemia.

CASE REPORT

A 71-year-old female patient diagnosed in 2005 with Waldenstrom macroglobulinemia was treated with cytostatics for eight years and in the period from September 2013 to March 2014 with six courses of rituximab. Afterwards, in April 2014 she presented with mental confusion, amnesia, visual disturbances, insomnia, dysphagia, dysarthria and right-sided central hemiparesis. Several times she had experienced trismus and clonic seizures of the extremities. The changes in her condition were noticed and reported by her relatives. Consequently, she was admitted to the Neurology Department. At neurological examination the Marinesku-Radovich and Babinski reflexes were present bilaterally; quadriparesis, pseudobulbar, and psychoorganic syndromes were confirmed and central right facial nerve paralysis was observed. The computer tomography (64 MDCT Lightspeed, GEHC) showed hypodense ill-defined subcortical lesions in the left frontal and both occipital lobes, in the splenium of corpus callosum, and in the left capsula interna. No real mass-effect was detected, but the involved gyri were mildly swollen (Fig.1).

Figure 1. Axial CT image shows hypodense ill-defined lesions without mass effect in both occipital lobes and in the splenium of corpus callosum

The magnetic resonance imaging (MRI Signa 1,5T, GEHC) revealed on T2WI and T2 FLAIR hyperintense, asymmetric bilateral white matter lesions in the subcortical and periventricular regions of the frontal, parietal and occipital lobes, along with centrum semiovale and corpus callosum (Figs. 2a, 2b and 2c).

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Progressive multifocal leukoencephalopathy in a non-HIV patient – A case r Szerző:Branimir Penev, Galina Kirova, Gloria Adam, Ivan Staikov www.radiologia.hu

c Figure 2. Axial (a, b) and sagittal (c) different pulse sequences show hyperintense on T2WI and hypointense on T1WI, asymmetric and confluent white matter lesions in the subcortical and periventricular regions of the frontal, parietal and occipital lobes, basal ganglia, left internal capsule, along with centrum semiovale and corpus callosum

Involvement of U-fibers was noticed (Fig. 3).

Figure 3. Coronal T2 FLAIR shows the involvement of U-fibers, the right cerebellar peduncle and the right cerebellar hemispheric white matter. Moreover, swelling of the affected gyri is seen

Other lesions were seen in the basal ganglia and the left internal capsule (Fig. 2b). The lesions in the basal ganglia could be interpreted in differential diagnosis as lacunar infarcts. Moreover, identical abnormal zones were seen in the subtentorial region – in the right cerebellar peduncle and in the right cerebellar hemispheric white matter (Fig. 3). All lesions were hypointese on T1WI (Fig. 2c). On T1+CEno contrast enhancement was shown. On DWI the pathologic zones showed a peripheral hyperintense rim (Fig. 4).

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Progressive multifocal leukoencephalopathy in a non-HIV patient – A case r Szerző:Branimir Penev, Galina Kirova, Gloria Adam, Ivan Staikov www.radiologia.hu

Figure 4. Axial DWI image shows the pathologic zones with peripheral diffusion restriction presented as a hyperintense rim

From the cerebrospinal fluid (CSF) examination the presence of John Cunningham virus (JCV) was detected and thereby the final diagnosis was made – progressive multifocal leukoencephalopathy (PML). Clinical condition worsened rapidly, with onset of respiratory failure, hemodynamic collapse and coma. Due to disease progression the patient died nine days after admission.

DISCUSSION

Progressive multifocal leukoencephalopathy is a rare infection of the central nervous system caused by the reactivation of the opportunistic JC virus (2). It is a brain demyelinating disease with high mortality rate if untreated, occurring in patients with immunosuppression – HIV, hematological malignancies, organ transplant recipients and people with chronic inflammatory conditions (3). The deoxyribonucleic acid (DNA) human polyomavirus JC (John Cunningham virus, JCV) is known for causing PML, just when reactivated (3). JCV infection is species-specific and it is found only in humans. At first, the disease was described in patients with lymphoproliferative disorders. The frequency of PML increased with the onset of HIV epidemic (4). In recent years, however, the use of monoclonal antibodies, like rituximab and natalizumab for the treatment of various conditions (multiple sclerosis, hematologic malignancies, Crohn’s disease, psoriasis, rheumatic arthritis and other autoimmune related diseases) has been associated with PML and increased the interest in the disease (2, 4). Typically, JC viruses affect oligodentrocytes and to a lesser extend astrocytes, which are being destroyed or sustain a productive infection. Studies show that the virus can be stored in different tissues throughout the body, where can persist latently or become reactivated, finally reaching the brain and causing PML (4). Classically, PML presents with focal neurological deficits that are related to location and size of the demyelinated areas in the brain. The symptoms are various and include progressive weakness, hemiparesis, dementia, sensory deficits, cognitive dysfunction, aphasia, cerebellar signs, like coordination and gait difficulties, bladder and bowel disturbances (4). The disease usually does not affect the optic nerves or the spinal cord. Some patients are reported to have developed seizures, due to the lesions adjacent to the cortex (3). The PML affected brain has multiple areas of demyelination, which are various in size and stage of evolution (3). CT is usually the first modality, but it is not specific. The lesions are observed as hypodense, ill-defined, and without mass-effect (4). MRI is the most sensitive diagnostic tool in the detection of PML and reveals bilateral, asymmetric lesions, which are hyperintense on T2 - weighted and T2 FLAIR images, and hypointense on T1- weighted images (T1WIs) (1). Any part of the brain can be affected, but lesions are commonly found in the subcortical white matter, the white matter of the cerebellar peduncles or hemispheres and in the brain stem. Furthermore, U-fibers are usually involved. The lesions are often multiple and tend to fuse.

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Progressive multifocal leukoencephalopathy in a non-HIV patient – A case r Szerző:Branimir Penev, Galina Kirova, Gloria Adam, Ivan Staikov www.radiologia.hu

PML affected zones in the later state of the disease can also be found in grey matter structures, such as the basal ganglia, due to the fact that they contain myelinated fibers (3, 4). The absence of mass-effect but swelling of the affected gyri and the lack of contrast enhancement is a characteristic feature for PML. In some cases (non HIV patients) a peripheral contrast enhancement is observed which is related to inflammatory reaction and is regarded as a predictive factor for prolonged survival. As the disease progresses, the lesions become more hypointense on T1WI. The diffusion-weighted imaging is important for the diagnosis of PML because detects areas with acute and active infection that leads to cell swelling. There is a typical DWI appearance – rim-like restriction of diffusion in the active lesion’s periphery (1). However, the finaldiagnosis is difficult because imaging findings can mimic other diseases and cause confusion. Differential diagnosis of PML is made with several conditions: acute disseminated encephalomyelitis (ADEM), posterior reversible encephalopathy syndrome (PRESS), multiple sclerosis and other viral infections – related leukoencephalopathy (1). PML is highly suspected in immunodeficient patients with focal neurological deficits and demyelinating lesions on MRI, which vary in size and stage of evolution. However, the definite diagnosis is made by the identification of JCV or proteins by in situ hybridization (ISH) or by immunohistochemistry staining (IHC) on brain biopsy, or by detection of JCV DNA in CSF by PCR (3, 4). It is important to make the diagnosis in a timely manner in order to with draw the exogenous immunosuppression and restore the host immune response to JCV, and thus stop the advance of disease (1, 4). It is recommended to use steroids during the early stage of treatment when the immune system begins to recover in order to prevent the development of immune reconstitution inflammatory syndrome (IRIS) and further destruction of the white matter. MRI is an important imaging modality which helps us set the accurate diagnosis and start the treatment.

CONCLUSION

PML is a rare demyelinating disease, which is caused by the John Cunningham virus in cases with immunodeficiency. The onset of the disease should be considered in deterioration of clinical condition in patients who are on treatment with monoclonal antibodies. PML has a high mortality rate that can be reduced by the prompt and correct diagnosis and adequate management. The diagnosis should be considered and based on the clinical presentation, neurological examination, imaging findings and the identification of the virus in CSF using PCR or in material from biopsy.

Abbreviations: ADEM – acute disseminated encephalomyelitis CSF – cerebrospinal fluid CT – computer tomography DNA – deoxyribonucleic acid DWI – diffusion weighted imaging FLAIR – fluid attenuated inversion recovery HAART – highly active antiretroviral therapy

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Progressive multifocal leukoencephalopathy in a non-HIV patient – A case r Szerző:Branimir Penev, Galina Kirova, Gloria Adam, Ivan Staikov www.radiologia.hu

HIV – human immunodeficiency virus IRIS – immune reconstitution inflammatory syndrome IHC – immunohistochemistry staining ISH – situ hybridization JCV – John Cunningham virus MRI – magnetic resonance imaging PCR – polymerase chain reaction PML – progressive multifocal leukoencephalopathy PRES – posterior reversible encephalopathy syndrome T1WI – T1 weighted imaging T2WI – T2 weighted imaging

Conflict of interest disclosure: The authors state that this work has not received any funding and declare no conflicts of interest. Institutional Review Board approval was obtained.

References:

1. Wattjes MP, Barkhof F. Diagnosis of natalizumab-associated progressive multifocal leukoencephalopathy using MRI. Current Opinion Neurology 2014;27:260-70. 2. Baldwin KJ, Hogg JP.Progressive multifocal leukoencephalopathy in patients with multiple sclerosis. Current Opinion Neurology 2013;26:318-23. 3. Cinque P,Koralnik IJ,Gerevini S, Miro JM, et al.Progressive multifocal leukoencephalopathy complicating HIV-1 infection. Lancet Infectious Disease 2009;9:625-36. 4. Tan CS, Koralnik IJ.Beyond progressive multifocal leukoencephalopathy: expanded pathogenesis of JC virus infection in the central nervous system. Lancet Neurology 2010;9:425-37. Absztrakt: Progressive multifocal leukoencephalopathy (PML) is an opportunistic infection of the central nervous system caused by the John Cunningham virus in individuals with immunosuppression – HIV, hematologic malignancies and some diseases treated with monoclonal antibodies. The disease is characterized by progressive neurological deficits and by asymmetrical zones of demyelination in the brain observed with magnetic resonance. In this study, we report a case of

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Progressive multifocal leukoencephalopathy in a non-HIV patient – A case r Szerző:Branimir Penev, Galina Kirova, Gloria Adam, Ivan Staikov www.radiologia.hu

non-HIV 71-year-old female patient treated with rituximab that was diagnosed with PML. We provide a clinical and radiographic description of PML and highlight its relationship to the use of monoclonal antibodies and immunosuppression. Kulcsszavak: progressive multifocal leukoencephalopathy, magnetic resonance imaging, non-HIV, monoclonal antibody Article Title: Progressive multifocal leukoencephalopathy in a non-HIV patient – A case report Szerző munkahelye: dr. Branimir Penev, dr. Galina Kirova, dr. Gloria Adam: Tokuda Hospital Sofia, Radiology Department dr. Ivan Staikov: Tokuda Hospital Sofia, Neurology Department  Szerző e-mail címe: [email protected] Szerző levelezési címe: Dr. Galina Kirova Tokuda Hospital Sofia Department of Radiology 51B Vapzarov blvd 1407 Sofia

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