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Enterovirus 71 meningoencephalitis complicating rituximab therapy
Journal of the Neurological Sciences 305 (2011) 149–151
Contents lists available at ScienceDirect
Journal of the Neurological Sciences j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / j n s
Short communication
Enterovirus 71 meningoencephalitis complicating rituximab therapy Rebekah Ahmed a, Michael Buckland b, Leo Davies a, G. Michael Halmagyi a, Shannon L. Rogers c, Steven Oberste c, Michael H. Barnett a,d,⁎ a
Institute of Clinical Neurosciences, Royal Prince Alfred Hospital, University of Sydney, Sydney, Australia Department of Neuropathology, Royal Prince Alfred Hospital, Sydney, Australia Centers for Disease Control and Prevention, Atlanta, GA USA d Brain and Mind Research Institute, University of Sydney, Sydney, Australia b c
a r t i c l e
i n f o
Article history: Received 21 January 2011 Received in revised form 28 February 2011 Accepted 1 March 2011 Available online 27 March 2011 Keywords: Enterovirus 71 Encephalitis Rituximab Monoclonal antibody
a b s t r a c t We describe a fatal case of proven enterovirus 71 meningoencephalitis complicating monoclonal anti-CD20 antibody therapy for non-Hodgkin's lymphoma. B-cell depletion, an effective treatment strategy in an expanding spectrum of hematological and inflammatory disorders, impairs neutralising antibody-mediated clearance of enterovirus. The global threat of emerging neurotropic viruses such as enterovirus 71 is heightened by an increasing pool of susceptible individuals in non-endemic regions. © 2011 Elsevier B.V. All rights reserved.
1. Introduction Viruses of the Enterovirus genus (family Picornaviridae) commonly cause self-limiting hand, foot and mouth disease (HFMD) or mild meningitis. However, enterovirus 71 (EV71) may cause catastrophic neurological disease in a small proportion of infected individuals. Sporadic cases and outbreaks of EV71 infection have been reported worldwide, and the virus has become prevalent in many parts of the Asia-Pacific region in the last decade. Clearance of enteroviruses is mediated by neutralising antibodies and may be impeded by B-cell immunodeficiency. We describe a fatal case of proven EV71 meningoencephalitis complicating therapy with the chimeric antiCD20 monoclonal antibody, rituximab. Increasing global patient exposures to B-cell depleting therapies heightens the threat of emerging neurotropic viruses and mandates increased vigilance in non-endemic regions. 2. Case history A 63 year old male presented with a one day history of fever, rigors, headache and right leg weakness 23 days after returning from a five day holiday in Phuket, Thailand. Worsening right hemiparesis, irregular myoclonic jerks of the right upper and lower limb and
⁎ Corresponding author. Brain and Mind Research Institute, Lvl 4, 94 Mallett Street, Camperdown NSW, Australia 2050. Tel.: +61 2 93510730; fax: +61 2 93510653. E-mail address: [email protected] (M.H. Barnett). 0022-510X/$ – see front matter © 2011 Elsevier B.V. All rights reserved. doi:10.1016/j.jns.2011.03.009
expressive aphasia ensued over the subsequent week, culminating in obtundation requiring ventilatory support. There was a past history of non-Hodgkin's lymphoma (NHL), treated with four cycles of rituximab the last administered three months prior to presentation; and maintenance therapy with prednisone 25 mg second daily. The patient's immunoglobulin levels were depleted at presentation: IgA 0.56 g/L (0.70–3.12), IgG 4.76 g/L (6.39–15.60), and IgM 0.28 g/L (0.50–3.00). Cerebrospinal fluid (CSF) was examined at 4 and 24 days. A minor lymphocytic pleocytosis was present in both samples and both were positive for enterovirus RNA by PCR. Magnetic resonance imaging (MRI) four days after symptom onset showed T2 signal hyperintensity and associated restricted diffusion in the left thalamus; and asymmetrically restricted diffusion in the posterior frontal gyri in the absence of discernable T2 signal change (Fig. 1 A,B). Twenty-four days after symptom onset, these changes had largely resolved and widespread global atrophy was evident (Fig. 1 C,D). Surgical biopsy of the left frontal cortex, 33 days after symptom onset, showed a mild meningopanencephalitis with reactive gliosis but no appreciable neuronal loss (Fig. 2 A,B,C,D). Despite therapy with intravenous immunoglobulin (IVIg) the patient succumbed twelve weeks after symptom onset. 3. Detection and identification of enterovirus 71 Reverse transcription and semi-nested PCR were performed on CSF by using primers in the enterovirus VP3 and VP1 genes in PCR1, followed by a second PCR reaction containing primers within VP1, as described previously [1]. The resulting DNA templates were
150
R. Ahmed et al. / Journal of the Neurological Sciences 305 (2011) 149–151
Fig. 1. A,B. Axial brain magnetic resonance diffusion-weighted imaging four days after symptom onset: subtle hyperintensity (arrowheads) is present in the left thalamus (A) and posterior frontal cortex (B). C,D. Coronal brain FLAIR sequences on days 4 (C) and 24 (D) after symptom onset: severe global atrophy is present on the later scan.
purified and sequenced with the PCR2 primers. Amplicon sequences were compared with the VP1 sequences of enterovirus reference strains, including at least one representative of each recognised serotype. In this scheme, a partial VP1 nucleotide sequence identity of N75% confirms the enterovirus serotype present in the specimen [2]. Partial genomic sequencing [1] identified the strain as EV71. Comparison of the sequence to those of other strains available in GenBank showed that it was closely related to strains of EV71 genotype C2 that have circulated in recent years in both Asia and Europe. 4. Discussion EV71 infection commonly causes hand, foot and mouth disease or mild meningitis, primarily in children. Mediated by a lytic infection of neurons, EV71 may, however, be associated with a destructive rhombencephalitis causing permanent neurologic sequelae or death [3]. In the present case, the EV71 sequence was 95% to 97% identical to those of strains reported in Southeast Asia, Europe and the United States in 2004–2008 suggesting that the strain is widely distributed and continues to circulate [4–6]. Rituximab, a chimeric anti-CD20 monoclonal antibody, is used for the treatment of B cell lymphoma and an expanding spectrum of autoimmune diseases [7]. Over 1,000,000 patient-exposures have
been recorded to date (http://www.rituxan.com). Sustained depletion of B cells may follow standard therapy [8] and opportunistic CNS infection is a recognised complication. Intact humoral immunity is required to clear enterovirus infection and CNS infection may be controlled by neutralising antibodies secreted by plasma cell clones in Virchow-Robin spaces or elsewhere within the CNS. Four cases of enterovirus meningoencephalitis complicating rituximab treatment of haematological disease have been previously reported [9–11]. Of these, two patients succumbed to the disease [10,11], and two suffered permanent neurological sequelae [9]. A causative enterovirus strain (echovirus 13) was identified in only one case [9]. To our knowledge, this is the first report of proven EV71 meningoencephalitis complicating rituximab therapy. Although brain MR imaging showed only subtle focal cortical and basal ganglia signal alteration at presentation, an unrelenting clinical decline, despite therapy with IVIg, was mirrored in the progress MR imaging, which showed dramatic global cerebral atrophy at day 24; and the brain histopathology, which showed ongoing inflammation and gliosis. Other than clinical suspicion based on previous rituximab therapy, there was little to indicate enterovirus infection in our patient. The minor CSF abnormalities were non-specific; and variable CSF findings in previously reported cases (Table 1) suggest that no single parameter can be used to direct specific testing for enterovirus infection.
R. Ahmed et al. / Journal of the Neurological Sciences 305 (2011) 149–151
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Fig. 2. A,B. Hematoxylin- and eosin-stained sections of the left frontal brain biopsy show a mild perivascular (A) and interstitial (A,B) mononuclear inflammatory cell infiltrate, and occasional microglial nodules (B). The mononuclear cells were predominantly CD3-positive T cells (C), and CD68-positive microglia (D). Magnification = 200× (A) and 400× (B,C,D).
Table 1 CSF findings in enterovirus meningoencephalitis following rituximab treatment. Age/sex
Underlying condition
CSF protein (g/L)
CSF white cell count (mm3)/% lymphocytes
Enterovirus PCR/strain
10/male9 53/NS9 75/male10 42/male11 63/malea
ITP Follicular lymphoma Non-Hodgkin lymphoma Large B cell lymphoma Non-Hodgkin lymphoma
0.34–0.94 1.2 NS 0.80 0.55 (day 4) 0.42 (day 24)
27–33/100% 300/NS 10/NS 10/69% 3/100% (day 4) 8/100% (day 24)
POS/NS POS/Echovirus 13 POS/NS POS/NS POS/EV71
NS = not stated; ITP = immune thrombocytopaenic purpura. a Present case.
While there is no therapy of proven efficacy for enterovirus meningoencephalitis, IVIg was used in all published cases that complicated rituximab therapy. The two surviving patients also received treatment with pleconaril [9], a small molecule antiviral that prevents the uptake of enterovirus into host cells. Pleconaril, whose efficacy against EV71 is doubtful [12], was declined a license by the US Food and Drug Administration in 2003 and is not currently commercially available. Vigilance for enterovirus infection should be exercised, and early IVIg therapy considered, in all symptomatic patients treated with rituximab. References [1] Nix WA, Oberste MS, Pallansch MA. Seminested PCR amplification of VP1 sequences for direct identification of all enterovirus serotypes from original clinical specimens. J Clin Microbiol 2006;44:2698–704. [2] Oberste MS, Pallansch MA. Enterovirus molecular detection and molecular typing. Rev Med Microbiol 2005;16:163–71. [3] Huang CC, Liu CC, Chang YC, Chen CY, Wang ST, Yeh TF. Neurologic complications in children with enterovirus 71 infection. NEJM 1999;341:936–42.
[4] Leitch EC, Harvala H, Robertson I, Ubillos I, Tempelton K, Simmonds P. Direct identification of human enterovirus serotypes in cerebrospinal fluid by amplification and sequencing of the VP1 region. J Clin Virol 2009;44:119–24. [5] Van der Sanden S, Koopmans M, Uslu G, Van der Avoort H. Epidemiology of enterovirus 71 in the Netherlands, 1963 to 2008. J Clin Microbiol 2009;47:2826–33. [6] Perez-Velez CM, Anderson MS, Robinson CC, Mcfarland EJ, Nix WA, Pallansch MA, et al. Outbreak of neurologic enterovirus type 71 disease: a diagnostic challenge. Clin Infect Dis 2007;45:950–7. [7] Pescovitz MD. Rituximab, an anti-CD20 monoclonal antibody: history and mechanism of action. Am J Transplant 2006;6:859–66. [8] McLaughlin P, Grillo-Lopez A, Link BK, Czuczman MS, Williams ME, Heyman MR, Bence-Bucker I, White CA, Cabanillas F, Jain V, Ho AD, Lister J, Wey K, Shen D, Dallaire BK. Rituximab chimeric anti-CD20 monoclonal antibody therapy for relapsed indolent lymphoma: half of patients respond to four-dose treatment program. J Clin Oncol 1998;16:2825–33. [9] Quartier P, Tournilhac O, Archimbaud C, Lazaro L, Chaleteix C, Miller P, et al. Enteroviral meningoencephalitis after anti-CD20 (rituximab) treatment. Clin Infect Dis 2003;36:47–9. [10] Padate BP, Keidan J. Enteroviral meningoencephalitis in a patient with non-Hodgkin's lymphoma treated previously with rituximab. Clin Lab Haem 2006;28:69–71. [11] Ganjoo KN, Raghan R, Sobel RA, Pinto H. Opportunistic enteroviral meningoencephalitis: an unusual treatable complication of rituximab therapy. Leuk Lymphoma 2009;50:673–5. [12] McMinn P. An overview of the evolution of enterovirus 71 and its clinical and public health significance. FEMS Microbiol Rev 2002;26:91–107.
Contents lists available at ScienceDirect
Journal of the Neurological Sciences j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / j n s
Short communication
Enterovirus 71 meningoencephalitis complicating rituximab therapy Rebekah Ahmed a, Michael Buckland b, Leo Davies a, G. Michael Halmagyi a, Shannon L. Rogers c, Steven Oberste c, Michael H. Barnett a,d,⁎ a
Institute of Clinical Neurosciences, Royal Prince Alfred Hospital, University of Sydney, Sydney, Australia Department of Neuropathology, Royal Prince Alfred Hospital, Sydney, Australia Centers for Disease Control and Prevention, Atlanta, GA USA d Brain and Mind Research Institute, University of Sydney, Sydney, Australia b c
a r t i c l e
i n f o
Article history: Received 21 January 2011 Received in revised form 28 February 2011 Accepted 1 March 2011 Available online 27 March 2011 Keywords: Enterovirus 71 Encephalitis Rituximab Monoclonal antibody
a b s t r a c t We describe a fatal case of proven enterovirus 71 meningoencephalitis complicating monoclonal anti-CD20 antibody therapy for non-Hodgkin's lymphoma. B-cell depletion, an effective treatment strategy in an expanding spectrum of hematological and inflammatory disorders, impairs neutralising antibody-mediated clearance of enterovirus. The global threat of emerging neurotropic viruses such as enterovirus 71 is heightened by an increasing pool of susceptible individuals in non-endemic regions. © 2011 Elsevier B.V. All rights reserved.
1. Introduction Viruses of the Enterovirus genus (family Picornaviridae) commonly cause self-limiting hand, foot and mouth disease (HFMD) or mild meningitis. However, enterovirus 71 (EV71) may cause catastrophic neurological disease in a small proportion of infected individuals. Sporadic cases and outbreaks of EV71 infection have been reported worldwide, and the virus has become prevalent in many parts of the Asia-Pacific region in the last decade. Clearance of enteroviruses is mediated by neutralising antibodies and may be impeded by B-cell immunodeficiency. We describe a fatal case of proven EV71 meningoencephalitis complicating therapy with the chimeric antiCD20 monoclonal antibody, rituximab. Increasing global patient exposures to B-cell depleting therapies heightens the threat of emerging neurotropic viruses and mandates increased vigilance in non-endemic regions. 2. Case history A 63 year old male presented with a one day history of fever, rigors, headache and right leg weakness 23 days after returning from a five day holiday in Phuket, Thailand. Worsening right hemiparesis, irregular myoclonic jerks of the right upper and lower limb and
⁎ Corresponding author. Brain and Mind Research Institute, Lvl 4, 94 Mallett Street, Camperdown NSW, Australia 2050. Tel.: +61 2 93510730; fax: +61 2 93510653. E-mail address: [email protected] (M.H. Barnett). 0022-510X/$ – see front matter © 2011 Elsevier B.V. All rights reserved. doi:10.1016/j.jns.2011.03.009
expressive aphasia ensued over the subsequent week, culminating in obtundation requiring ventilatory support. There was a past history of non-Hodgkin's lymphoma (NHL), treated with four cycles of rituximab the last administered three months prior to presentation; and maintenance therapy with prednisone 25 mg second daily. The patient's immunoglobulin levels were depleted at presentation: IgA 0.56 g/L (0.70–3.12), IgG 4.76 g/L (6.39–15.60), and IgM 0.28 g/L (0.50–3.00). Cerebrospinal fluid (CSF) was examined at 4 and 24 days. A minor lymphocytic pleocytosis was present in both samples and both were positive for enterovirus RNA by PCR. Magnetic resonance imaging (MRI) four days after symptom onset showed T2 signal hyperintensity and associated restricted diffusion in the left thalamus; and asymmetrically restricted diffusion in the posterior frontal gyri in the absence of discernable T2 signal change (Fig. 1 A,B). Twenty-four days after symptom onset, these changes had largely resolved and widespread global atrophy was evident (Fig. 1 C,D). Surgical biopsy of the left frontal cortex, 33 days after symptom onset, showed a mild meningopanencephalitis with reactive gliosis but no appreciable neuronal loss (Fig. 2 A,B,C,D). Despite therapy with intravenous immunoglobulin (IVIg) the patient succumbed twelve weeks after symptom onset. 3. Detection and identification of enterovirus 71 Reverse transcription and semi-nested PCR were performed on CSF by using primers in the enterovirus VP3 and VP1 genes in PCR1, followed by a second PCR reaction containing primers within VP1, as described previously [1]. The resulting DNA templates were
150
R. Ahmed et al. / Journal of the Neurological Sciences 305 (2011) 149–151
Fig. 1. A,B. Axial brain magnetic resonance diffusion-weighted imaging four days after symptom onset: subtle hyperintensity (arrowheads) is present in the left thalamus (A) and posterior frontal cortex (B). C,D. Coronal brain FLAIR sequences on days 4 (C) and 24 (D) after symptom onset: severe global atrophy is present on the later scan.
purified and sequenced with the PCR2 primers. Amplicon sequences were compared with the VP1 sequences of enterovirus reference strains, including at least one representative of each recognised serotype. In this scheme, a partial VP1 nucleotide sequence identity of N75% confirms the enterovirus serotype present in the specimen [2]. Partial genomic sequencing [1] identified the strain as EV71. Comparison of the sequence to those of other strains available in GenBank showed that it was closely related to strains of EV71 genotype C2 that have circulated in recent years in both Asia and Europe. 4. Discussion EV71 infection commonly causes hand, foot and mouth disease or mild meningitis, primarily in children. Mediated by a lytic infection of neurons, EV71 may, however, be associated with a destructive rhombencephalitis causing permanent neurologic sequelae or death [3]. In the present case, the EV71 sequence was 95% to 97% identical to those of strains reported in Southeast Asia, Europe and the United States in 2004–2008 suggesting that the strain is widely distributed and continues to circulate [4–6]. Rituximab, a chimeric anti-CD20 monoclonal antibody, is used for the treatment of B cell lymphoma and an expanding spectrum of autoimmune diseases [7]. Over 1,000,000 patient-exposures have
been recorded to date (http://www.rituxan.com). Sustained depletion of B cells may follow standard therapy [8] and opportunistic CNS infection is a recognised complication. Intact humoral immunity is required to clear enterovirus infection and CNS infection may be controlled by neutralising antibodies secreted by plasma cell clones in Virchow-Robin spaces or elsewhere within the CNS. Four cases of enterovirus meningoencephalitis complicating rituximab treatment of haematological disease have been previously reported [9–11]. Of these, two patients succumbed to the disease [10,11], and two suffered permanent neurological sequelae [9]. A causative enterovirus strain (echovirus 13) was identified in only one case [9]. To our knowledge, this is the first report of proven EV71 meningoencephalitis complicating rituximab therapy. Although brain MR imaging showed only subtle focal cortical and basal ganglia signal alteration at presentation, an unrelenting clinical decline, despite therapy with IVIg, was mirrored in the progress MR imaging, which showed dramatic global cerebral atrophy at day 24; and the brain histopathology, which showed ongoing inflammation and gliosis. Other than clinical suspicion based on previous rituximab therapy, there was little to indicate enterovirus infection in our patient. The minor CSF abnormalities were non-specific; and variable CSF findings in previously reported cases (Table 1) suggest that no single parameter can be used to direct specific testing for enterovirus infection.
R. Ahmed et al. / Journal of the Neurological Sciences 305 (2011) 149–151
151
Fig. 2. A,B. Hematoxylin- and eosin-stained sections of the left frontal brain biopsy show a mild perivascular (A) and interstitial (A,B) mononuclear inflammatory cell infiltrate, and occasional microglial nodules (B). The mononuclear cells were predominantly CD3-positive T cells (C), and CD68-positive microglia (D). Magnification = 200× (A) and 400× (B,C,D).
Table 1 CSF findings in enterovirus meningoencephalitis following rituximab treatment. Age/sex
Underlying condition
CSF protein (g/L)
CSF white cell count (mm3)/% lymphocytes
Enterovirus PCR/strain
10/male9 53/NS9 75/male10 42/male11 63/malea
ITP Follicular lymphoma Non-Hodgkin lymphoma Large B cell lymphoma Non-Hodgkin lymphoma
0.34–0.94 1.2 NS 0.80 0.55 (day 4) 0.42 (day 24)
27–33/100% 300/NS 10/NS 10/69% 3/100% (day 4) 8/100% (day 24)
POS/NS POS/Echovirus 13 POS/NS POS/NS POS/EV71
NS = not stated; ITP = immune thrombocytopaenic purpura. a Present case.
While there is no therapy of proven efficacy for enterovirus meningoencephalitis, IVIg was used in all published cases that complicated rituximab therapy. The two surviving patients also received treatment with pleconaril [9], a small molecule antiviral that prevents the uptake of enterovirus into host cells. Pleconaril, whose efficacy against EV71 is doubtful [12], was declined a license by the US Food and Drug Administration in 2003 and is not currently commercially available. Vigilance for enterovirus infection should be exercised, and early IVIg therapy considered, in all symptomatic patients treated with rituximab. References [1] Nix WA, Oberste MS, Pallansch MA. Seminested PCR amplification of VP1 sequences for direct identification of all enterovirus serotypes from original clinical specimens. J Clin Microbiol 2006;44:2698–704. [2] Oberste MS, Pallansch MA. Enterovirus molecular detection and molecular typing. Rev Med Microbiol 2005;16:163–71. [3] Huang CC, Liu CC, Chang YC, Chen CY, Wang ST, Yeh TF. Neurologic complications in children with enterovirus 71 infection. NEJM 1999;341:936–42.
[4] Leitch EC, Harvala H, Robertson I, Ubillos I, Tempelton K, Simmonds P. Direct identification of human enterovirus serotypes in cerebrospinal fluid by amplification and sequencing of the VP1 region. J Clin Virol 2009;44:119–24. [5] Van der Sanden S, Koopmans M, Uslu G, Van der Avoort H. Epidemiology of enterovirus 71 in the Netherlands, 1963 to 2008. J Clin Microbiol 2009;47:2826–33. [6] Perez-Velez CM, Anderson MS, Robinson CC, Mcfarland EJ, Nix WA, Pallansch MA, et al. Outbreak of neurologic enterovirus type 71 disease: a diagnostic challenge. Clin Infect Dis 2007;45:950–7. [7] Pescovitz MD. Rituximab, an anti-CD20 monoclonal antibody: history and mechanism of action. Am J Transplant 2006;6:859–66. [8] McLaughlin P, Grillo-Lopez A, Link BK, Czuczman MS, Williams ME, Heyman MR, Bence-Bucker I, White CA, Cabanillas F, Jain V, Ho AD, Lister J, Wey K, Shen D, Dallaire BK. Rituximab chimeric anti-CD20 monoclonal antibody therapy for relapsed indolent lymphoma: half of patients respond to four-dose treatment program. J Clin Oncol 1998;16:2825–33. [9] Quartier P, Tournilhac O, Archimbaud C, Lazaro L, Chaleteix C, Miller P, et al. Enteroviral meningoencephalitis after anti-CD20 (rituximab) treatment. Clin Infect Dis 2003;36:47–9. [10] Padate BP, Keidan J. Enteroviral meningoencephalitis in a patient with non-Hodgkin's lymphoma treated previously with rituximab. Clin Lab Haem 2006;28:69–71. [11] Ganjoo KN, Raghan R, Sobel RA, Pinto H. Opportunistic enteroviral meningoencephalitis: an unusual treatable complication of rituximab therapy. Leuk Lymphoma 2009;50:673–5. [12] McMinn P. An overview of the evolution of enterovirus 71 and its clinical and public health significance. FEMS Microbiol Rev 2002;26:91–107.