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Progressive multifocal leukoencephalopathy presenting as a single ring-enhancing lesion
Clinical Neurology and Neurosurgery 122 (2014) 77–79
Contents lists available at ScienceDirect
Clinical Neurology and Neurosurgery journal homepage: www.elsevier.com/locate/clineuro
Case report
Progressive multifocal leukoencephalopathy presenting as a single ring-enhancing lesion Branko Skovrlj a, * , Jonathan Rasouli a , John Caridi a , William M. Taylor b , Daniel D. Galyon c a
Department of Neurosurgery, Mount Sinai School of Medicine, New York, USA Department of Pathology, WellSpan York Hospital, York, USA c Department of Neurosurgery, Southern New York Neurosurgical Group, Binghamton, USA b
1. Introduction Progressive multifocal leukoencephalopathy (PML) is a slow evolving, demyelinating central nervous system (CNS) infection caused by the reactivation of the ubiquitous JC virus (JCV), a type of the human polyoma virus [1]. The typical appearance of the PML on neuroimaging studies consists of symmetric or asymmetric multifocal areas of white matter demyelination that do not conform to cerebrovascular territories and exhibit neither mass effect nor contrast enhancement [1]. Vanneste et al. [2], in 1984, described a case of the PML presenting as a single mass lesion on the computed tomography (CT). In 2008, Bonavita et al. [3] described a case of the PML presenting as an infratentorial, homogenously enhancing mass lesion on MRI. To our knowledge, this is the first case of the PML presenting as a single, ringenhancing, centrally necrotic, supratentorial lesion with surrounding vasogenic edema. 2. Case report An 85-year-old male with past medical history significant for Waldenstrom's macroglobulinemia of 18 months duration treated successfully with chemotherapy and prostate cancer of one-year duration treated successfully with cryotherapy presented with vague symptoms of imbalance and dizziness for approximately one year. The only findings on physical exam were absence of deep tendon reflexes in his lower extremities and slight numbness to touch and pinprick in the fingers of both hand; most likely secondary to a mild peripheral neuropathy associated with Waldenstrom's macroglobulinemia. A magnetic resonance imaging (MRI) scan of the brain revealed generalized cerebral atrophy and a 10 mm 13 mm 11 mm peripherally enhancing, centrally necrotic, ring-enhancing lesion at the temporo-occipital junction
* Corresponding author at: Department of Neurosurgery, Mount Sinai School of Medicine, 1 Gustave L. Levy Place, Box 1136, New York 10029, USA. Tel.: +1 212 241 6268/4044092049; fax: +1 212 241 7388. E-mail address: [email protected] (B. Skovrlj). http://dx.doi.org/10.1016/j.clineuro.2014.04.019 0303-8467/ ã 2014 Elsevier B.V. All rights reserved.
with surrounding vasogenic edema (Fig. 1). After discussion about possible diagnostic modalities and options for treatment, a decision was made for the patient to undergo an image guided biopsy of the lesion as concerns for metastatic disease or primary brain neoplasm were raised. Intraoperatively, two white-tan, soft cylindrical portions of tissue measuring 0.6 cm 0.2 cm and 0.7 cm 0.2 cm, respectively, were sent to pathology for analysis. The frozen section showed hypercellular brain parenchyma with atypical lymphoid cells around blood vessels and gliosis. Many large round nuclei (Fig. 2(A)) with viral cytopathic inclusions (Fig. 2(B)) and perivascular and intraparenchymal scattered benign lymphocytes were noted. Permanent paraffin section immunohistochemical stains showed reactive astrocytes positive for glial fibrillary acidic protein (GFAP) (Fig. 2(C)). Most of the lymphocytes were positive for T-cell markers (CD3) and for leukocyte common antigen (LCA). CD20 and CD79a (B-cell markers) highlighted few scattered lymphocytes. The large round nuclei with viral cytopathic effect had high MIB-1 index (Ki-67) as well as immunoreactivity for p53 and SV40 (Fig. 2(D)). A diagnosis of the PML was made, confirmed by the typical histopathologic findings of the PML and positive staining for the JCV in the brain biopsy tissue as well as confirmation of the diagnosis from an outside neuropathology consultation. Postbiopsy, the patient’s symptoms remained unchanged and he continued to complain of persistent dizziness. He was tested for the human immunodeficiency (HIV) virus and was tested negative. He refused any medical treatment for the PML. At the 12 month postoperative visit, the patient complained of continued dizziness that was better tolerated and new onset ataxia. A brain MRI performed at that time showed no change in the size or appearance of the lesion and no new lesions were appreciated. 3. Discussion The JCV, a DNA-based virus, is a type of human polyomavirus. It is ubiquitous in the general population, infecting 70–90% of humans [1]. Most people acquire the JCV in childhood or adolescence. It is found in high concentrations in metropolitan sewage worldwide, leading to the suspicion of contaminated water
78
B. Skovrlj et al. / Clinical Neurology and Neurosurgery 122 (2014) 77–79
Fig. 1. Preoperative (A) axial, (B) sagittal, and (C) coronal T-1 weighted contrast enhanced MRI images demonstrating a right-sided, temporo-occipital, ring-enhancing lesion measuring 10 mm 13 mm 11 mm with surrounding vasogenic edema.
as a typical route of the infection. The virus is typically acquired during childhood and the initial site of infection may be tonsils, or possibly the GI tract [4]. The virus remains latent in the gastrointestinal tract but can also infect the epithelial cells in the kidneys, where it continues to reproduce, shedding the virus particles in the urine [1]. The JCV can cross the blood–brain barrier into the central nervous system, where it infects oligodendrocytes and astrocytes, possibly through the 5-HT2A serotonin receptor [4]. The JCV can be readily found within the brain of asymptomatic individuals. The PML usually occurs in the patients with impaired cellmediated immunity [1]. Asymptomatic primary infection with the JCV occurs in childhood and antibodies can be found in 86% of adults [4]. More than 60% of currently diagnosed PML cases are seen in the patients with acquired immunodeficiency syndrome (AIDS) [5]. Previously, the AIDS epidemic lymphoproliferative disease was the most common cause of the PML [4]. The PML is usually fatal, and the median survival of the patients without the HIV infection is only 2.6 months. In patients with the HIV infection
and PML, the median survival for patients has increased from 0.4 years in the era before highly active antiretroviral therapy (HAART) to 1.8 years with widespread use of HAART [5]. The patients often present with a variety of symptoms related to mental functioning. Clumsiness is often the first symptom and hemiparesis is the most common finding. Cognitive impairment is seen in more than 50% of the patients with multifocal cortical damage. Disorientation, lack of energy, confusion, loss of balance, unilateral weakness in the arms or legs, blurred or double vision, speech difficulties and loss of vision in one eye are known symptoms directly related to the damage caused to the oligodendrocytes and the subsequent demyelination of axons within the CNS [1]. In addition to demyelination, there are characteristic cytologic alterations in both the astrocytes and oligodendrocytes. Astrocytes are significantly enlarged and contain bizarre, hyperchromatic and deformed nuclei with frequent mitotic figures that resemble astrocytes that can be seen in glioblastomas [4]. Oligodendrocytes have enlarged, densely staining nuclei that contain viral inclusion
Fig. 2. (A) Low power, viral inclusions (ground-glass appearance typical of oligodendrocytes infected by polyomavirus; arrow) and gliosis (hematoxylin-eosin, original magnification 200). (B) High power, mitotic figure (asterics) adjacent to viral nuclear inclusion (arrow), (hematoxylin-eosin, original magnification 400). (C) Low power, glial fibrillary acidic protein (GFAP) showing reactive astrocytes (arrow), (immunohistochemical stain, original magnification 200). (D) Low power, SV40 positive immunoreactivity showing dark nuclei of virally infected oligodendrocyte reacting with antibodies against JC virus (arrow), (immunohistochemical stain, original magnification 200).
B. Skovrlj et al. / Clinical Neurology and Neurosurgery 122 (2014) 77–79
bodies filled with crystalline arrangements of the JCV particles (Fig. 2(A,B)) [4]. Mitoses are rare and those that do occur may appear atypical (Fig. 2(B)). Despite the nuclear pleomorphism, the lesions can be easily differentiated from a neoplasm by their low cellularity and the presence of viral inclusions. The viral nucleic acids can be detected and identified by in situ hybridization [4]. The findings of neuronal loss, cell membrane and myelin breakdown and increased glial activity within the PML lesions can be interpreted with the magnetic resonance spectroscopy (MRS) and are characterized by reductions in N-acetylaspartate and creatinine, and by significant increase in the choline, lactate and lipids. MRS appears to be a helpful non-invasive diagnostic tool in the diagnosis of the PML. Our patient’s medical history and initial findings on the MRI imaging directed our attention towards the most frequently encountered causes of a single, centrally necrotic, ring-enhancing lesion, including the metastasis, abscess, and glioblastoma multiforme. Our initial concerns were that of the CNS metastasis from the previously treated prostate cancer or a possibility of the CNS lymphoma. The duration of the patient’s symptoms together with the stable and non-progressing status of his disease, coupled with the findings on the MRI imaging made the initial diagnosis puzzling. The patient’s positive health status more than two years since the initial onset of his dizziness, added another intriguing twist to our case. With a definitive diagnosis of the PML, confirmed by the typical histopathologic findings of the PML and positive staining for the JCV in the surgical specimen together with a confirmation of the diagnosis from an outside neuropathology consultation, we are left to wonder what the initial insult was to the immune system that allowed for the JC virus to activate itself in this patient’s brain. Our patient was elderly and suffered from Waldenstrom's macroglobulinemia, a B-cell cancer that results in a dysfunctional cellular immune system. It is possible that his weakened cellular immune system led to the initial activation of the JCV within his brain or its spread from a distant organ system to the CNS. The subsequent chemotherapy that our patient received as part of the treatment of the macroglobulinemia likely further
79
weakened his immune system and lead to uncontrolled JCV replication resulting in the lesion formation. Following successful treatment of the macroglobulinemia and the subsequent recovery of our patient's immune system, the JCV was likely contained within the single lesion nidus and remained latent at that location.
4. Conclusion Very little is understood about the pathogenesis of the JCV and even less literature is available on the select cases of the PML in non-AIDS patients. This patient’s unexpected presentation and pathological findings allow for valuable diagnostic and histopathologic evidence to be collected on this unusual presentation of this rare and unique disease. We now have the evidence to suggest that the rare cases of the PML can present as a single, centrally necrotic, ring-enhancing lesion and that the PML should be considered in any immunocompromised patient with such a lesion in the brain. With these findings, we expand the differential diagnosis list of possible causes of a single, centrally necrotic, ring-enhancing lesion in the brain of an immunocompromised individual to include the PML.
References [1] Koralnik IJ. In: Gonzalez-Scarano F, editor. Progressive multifocal leukoencephalopathy: epidemiology, clinical manifestations, and diagnosis. Available from http://www.uptodate.com. [accessed April 2013]. [2] Vanneste JA, Bellot SM, Stam FC. Progressive multifocal leukoencephalopathy presenting as a single mass lesion. Eur Neurol 1984;23(2):113–8. [3] Bonavita S, Conforti R, Russo A, Sacco R, Tessitore A, Gallo A, et al. Infratentorial progressive multifocal leukoencephalopathy in a patient treated with fludarabine and rituximab. Neurol Sci 2008;29(1):37–9. [4] Ferenczy MW, Marshall LJ, Nelson CD, Atwood WJ, Nath A, Khalili K, et al. Molecular biology, epidemiology, and pathogenesis of progressive multifocal leukoencephalopathy, the JC virus-induced demyelinating disease of the human brain. Clin Microbiol Rev 2012;25(3):471–506. [5] Clinque P, Koralnik IJ, Gerevini S, Miro JM, Price RW. Progressive multifocal leukencephalopathy in HIV-1 infection. Lancet Infect Dis 2009;9(10):625–36.
Contents lists available at ScienceDirect
Clinical Neurology and Neurosurgery journal homepage: www.elsevier.com/locate/clineuro
Case report
Progressive multifocal leukoencephalopathy presenting as a single ring-enhancing lesion Branko Skovrlj a, * , Jonathan Rasouli a , John Caridi a , William M. Taylor b , Daniel D. Galyon c a
Department of Neurosurgery, Mount Sinai School of Medicine, New York, USA Department of Pathology, WellSpan York Hospital, York, USA c Department of Neurosurgery, Southern New York Neurosurgical Group, Binghamton, USA b
1. Introduction Progressive multifocal leukoencephalopathy (PML) is a slow evolving, demyelinating central nervous system (CNS) infection caused by the reactivation of the ubiquitous JC virus (JCV), a type of the human polyoma virus [1]. The typical appearance of the PML on neuroimaging studies consists of symmetric or asymmetric multifocal areas of white matter demyelination that do not conform to cerebrovascular territories and exhibit neither mass effect nor contrast enhancement [1]. Vanneste et al. [2], in 1984, described a case of the PML presenting as a single mass lesion on the computed tomography (CT). In 2008, Bonavita et al. [3] described a case of the PML presenting as an infratentorial, homogenously enhancing mass lesion on MRI. To our knowledge, this is the first case of the PML presenting as a single, ringenhancing, centrally necrotic, supratentorial lesion with surrounding vasogenic edema. 2. Case report An 85-year-old male with past medical history significant for Waldenstrom's macroglobulinemia of 18 months duration treated successfully with chemotherapy and prostate cancer of one-year duration treated successfully with cryotherapy presented with vague symptoms of imbalance and dizziness for approximately one year. The only findings on physical exam were absence of deep tendon reflexes in his lower extremities and slight numbness to touch and pinprick in the fingers of both hand; most likely secondary to a mild peripheral neuropathy associated with Waldenstrom's macroglobulinemia. A magnetic resonance imaging (MRI) scan of the brain revealed generalized cerebral atrophy and a 10 mm 13 mm 11 mm peripherally enhancing, centrally necrotic, ring-enhancing lesion at the temporo-occipital junction
* Corresponding author at: Department of Neurosurgery, Mount Sinai School of Medicine, 1 Gustave L. Levy Place, Box 1136, New York 10029, USA. Tel.: +1 212 241 6268/4044092049; fax: +1 212 241 7388. E-mail address: [email protected] (B. Skovrlj). http://dx.doi.org/10.1016/j.clineuro.2014.04.019 0303-8467/ ã 2014 Elsevier B.V. All rights reserved.
with surrounding vasogenic edema (Fig. 1). After discussion about possible diagnostic modalities and options for treatment, a decision was made for the patient to undergo an image guided biopsy of the lesion as concerns for metastatic disease or primary brain neoplasm were raised. Intraoperatively, two white-tan, soft cylindrical portions of tissue measuring 0.6 cm 0.2 cm and 0.7 cm 0.2 cm, respectively, were sent to pathology for analysis. The frozen section showed hypercellular brain parenchyma with atypical lymphoid cells around blood vessels and gliosis. Many large round nuclei (Fig. 2(A)) with viral cytopathic inclusions (Fig. 2(B)) and perivascular and intraparenchymal scattered benign lymphocytes were noted. Permanent paraffin section immunohistochemical stains showed reactive astrocytes positive for glial fibrillary acidic protein (GFAP) (Fig. 2(C)). Most of the lymphocytes were positive for T-cell markers (CD3) and for leukocyte common antigen (LCA). CD20 and CD79a (B-cell markers) highlighted few scattered lymphocytes. The large round nuclei with viral cytopathic effect had high MIB-1 index (Ki-67) as well as immunoreactivity for p53 and SV40 (Fig. 2(D)). A diagnosis of the PML was made, confirmed by the typical histopathologic findings of the PML and positive staining for the JCV in the brain biopsy tissue as well as confirmation of the diagnosis from an outside neuropathology consultation. Postbiopsy, the patient’s symptoms remained unchanged and he continued to complain of persistent dizziness. He was tested for the human immunodeficiency (HIV) virus and was tested negative. He refused any medical treatment for the PML. At the 12 month postoperative visit, the patient complained of continued dizziness that was better tolerated and new onset ataxia. A brain MRI performed at that time showed no change in the size or appearance of the lesion and no new lesions were appreciated. 3. Discussion The JCV, a DNA-based virus, is a type of human polyomavirus. It is ubiquitous in the general population, infecting 70–90% of humans [1]. Most people acquire the JCV in childhood or adolescence. It is found in high concentrations in metropolitan sewage worldwide, leading to the suspicion of contaminated water
78
B. Skovrlj et al. / Clinical Neurology and Neurosurgery 122 (2014) 77–79
Fig. 1. Preoperative (A) axial, (B) sagittal, and (C) coronal T-1 weighted contrast enhanced MRI images demonstrating a right-sided, temporo-occipital, ring-enhancing lesion measuring 10 mm 13 mm 11 mm with surrounding vasogenic edema.
as a typical route of the infection. The virus is typically acquired during childhood and the initial site of infection may be tonsils, or possibly the GI tract [4]. The virus remains latent in the gastrointestinal tract but can also infect the epithelial cells in the kidneys, where it continues to reproduce, shedding the virus particles in the urine [1]. The JCV can cross the blood–brain barrier into the central nervous system, where it infects oligodendrocytes and astrocytes, possibly through the 5-HT2A serotonin receptor [4]. The JCV can be readily found within the brain of asymptomatic individuals. The PML usually occurs in the patients with impaired cellmediated immunity [1]. Asymptomatic primary infection with the JCV occurs in childhood and antibodies can be found in 86% of adults [4]. More than 60% of currently diagnosed PML cases are seen in the patients with acquired immunodeficiency syndrome (AIDS) [5]. Previously, the AIDS epidemic lymphoproliferative disease was the most common cause of the PML [4]. The PML is usually fatal, and the median survival of the patients without the HIV infection is only 2.6 months. In patients with the HIV infection
and PML, the median survival for patients has increased from 0.4 years in the era before highly active antiretroviral therapy (HAART) to 1.8 years with widespread use of HAART [5]. The patients often present with a variety of symptoms related to mental functioning. Clumsiness is often the first symptom and hemiparesis is the most common finding. Cognitive impairment is seen in more than 50% of the patients with multifocal cortical damage. Disorientation, lack of energy, confusion, loss of balance, unilateral weakness in the arms or legs, blurred or double vision, speech difficulties and loss of vision in one eye are known symptoms directly related to the damage caused to the oligodendrocytes and the subsequent demyelination of axons within the CNS [1]. In addition to demyelination, there are characteristic cytologic alterations in both the astrocytes and oligodendrocytes. Astrocytes are significantly enlarged and contain bizarre, hyperchromatic and deformed nuclei with frequent mitotic figures that resemble astrocytes that can be seen in glioblastomas [4]. Oligodendrocytes have enlarged, densely staining nuclei that contain viral inclusion
Fig. 2. (A) Low power, viral inclusions (ground-glass appearance typical of oligodendrocytes infected by polyomavirus; arrow) and gliosis (hematoxylin-eosin, original magnification 200). (B) High power, mitotic figure (asterics) adjacent to viral nuclear inclusion (arrow), (hematoxylin-eosin, original magnification 400). (C) Low power, glial fibrillary acidic protein (GFAP) showing reactive astrocytes (arrow), (immunohistochemical stain, original magnification 200). (D) Low power, SV40 positive immunoreactivity showing dark nuclei of virally infected oligodendrocyte reacting with antibodies against JC virus (arrow), (immunohistochemical stain, original magnification 200).
B. Skovrlj et al. / Clinical Neurology and Neurosurgery 122 (2014) 77–79
bodies filled with crystalline arrangements of the JCV particles (Fig. 2(A,B)) [4]. Mitoses are rare and those that do occur may appear atypical (Fig. 2(B)). Despite the nuclear pleomorphism, the lesions can be easily differentiated from a neoplasm by their low cellularity and the presence of viral inclusions. The viral nucleic acids can be detected and identified by in situ hybridization [4]. The findings of neuronal loss, cell membrane and myelin breakdown and increased glial activity within the PML lesions can be interpreted with the magnetic resonance spectroscopy (MRS) and are characterized by reductions in N-acetylaspartate and creatinine, and by significant increase in the choline, lactate and lipids. MRS appears to be a helpful non-invasive diagnostic tool in the diagnosis of the PML. Our patient’s medical history and initial findings on the MRI imaging directed our attention towards the most frequently encountered causes of a single, centrally necrotic, ring-enhancing lesion, including the metastasis, abscess, and glioblastoma multiforme. Our initial concerns were that of the CNS metastasis from the previously treated prostate cancer or a possibility of the CNS lymphoma. The duration of the patient’s symptoms together with the stable and non-progressing status of his disease, coupled with the findings on the MRI imaging made the initial diagnosis puzzling. The patient’s positive health status more than two years since the initial onset of his dizziness, added another intriguing twist to our case. With a definitive diagnosis of the PML, confirmed by the typical histopathologic findings of the PML and positive staining for the JCV in the surgical specimen together with a confirmation of the diagnosis from an outside neuropathology consultation, we are left to wonder what the initial insult was to the immune system that allowed for the JC virus to activate itself in this patient’s brain. Our patient was elderly and suffered from Waldenstrom's macroglobulinemia, a B-cell cancer that results in a dysfunctional cellular immune system. It is possible that his weakened cellular immune system led to the initial activation of the JCV within his brain or its spread from a distant organ system to the CNS. The subsequent chemotherapy that our patient received as part of the treatment of the macroglobulinemia likely further
79
weakened his immune system and lead to uncontrolled JCV replication resulting in the lesion formation. Following successful treatment of the macroglobulinemia and the subsequent recovery of our patient's immune system, the JCV was likely contained within the single lesion nidus and remained latent at that location.
4. Conclusion Very little is understood about the pathogenesis of the JCV and even less literature is available on the select cases of the PML in non-AIDS patients. This patient’s unexpected presentation and pathological findings allow for valuable diagnostic and histopathologic evidence to be collected on this unusual presentation of this rare and unique disease. We now have the evidence to suggest that the rare cases of the PML can present as a single, centrally necrotic, ring-enhancing lesion and that the PML should be considered in any immunocompromised patient with such a lesion in the brain. With these findings, we expand the differential diagnosis list of possible causes of a single, centrally necrotic, ring-enhancing lesion in the brain of an immunocompromised individual to include the PML.
References [1] Koralnik IJ. In: Gonzalez-Scarano F, editor. Progressive multifocal leukoencephalopathy: epidemiology, clinical manifestations, and diagnosis. Available from http://www.uptodate.com. [accessed April 2013]. [2] Vanneste JA, Bellot SM, Stam FC. Progressive multifocal leukoencephalopathy presenting as a single mass lesion. Eur Neurol 1984;23(2):113–8. [3] Bonavita S, Conforti R, Russo A, Sacco R, Tessitore A, Gallo A, et al. Infratentorial progressive multifocal leukoencephalopathy in a patient treated with fludarabine and rituximab. Neurol Sci 2008;29(1):37–9. [4] Ferenczy MW, Marshall LJ, Nelson CD, Atwood WJ, Nath A, Khalili K, et al. Molecular biology, epidemiology, and pathogenesis of progressive multifocal leukoencephalopathy, the JC virus-induced demyelinating disease of the human brain. Clin Microbiol Rev 2012;25(3):471–506. [5] Clinque P, Koralnik IJ, Gerevini S, Miro JM, Price RW. Progressive multifocal leukencephalopathy in HIV-1 infection. Lancet Infect Dis 2009;9(10):625–36.