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Measles inclusion-body encephalitis (MIBE) in a immunocompromised patient
Journal of Clinical Virology 81 (2016) 43–46
Contents lists available at ScienceDirect
Journal of Clinical Virology journal homepage: www.elsevier.com/locate/jcv
Case report
Measles inclusion-body encephalitis (MIBE) in a immunocompromised patient Aurélie Baldolli a,∗ , Sylvie Dargère a , Erick Cardineau b , Astrid Vabret c , Julia Dina c , Arnaud de La Blanchardière a , Renaud Verdon a a
Department of Infectious Diseases, University Hospital of Caen, France Department of Nephrology, Hospital of Alenc¸on-Mamers, France c Department of Virology, French National Reference Laboratory for Measles, University Hospital of Caen, France b
a r t i c l e
i n f o
Article history: Received 11 April 2016 Received in revised form 26 May 2016 Accepted 30 May 2016 Keywords: Measles Inclusion-body encephalitis Microscopic polyangiitis
1. Why this case is important Although measles immunization programs are present in Europe, several countries reported outbreaks since 2006–2007. Our case emphasizes the dramatic consequences of suboptimal adherence to these programs.
2. Case report A 27-year-old teacher was hospitalized in 2010 in Caen, France, for decrease of visual acuity with evolution towards blindness. Her medical history was marked by a microscopic polyangiitis diagnosed in 2007 which was treated with mycophenolate mofetil plus prednisone since 2009. Only one dose of measles-rubella vaccine (Rudi-Rouvax® Schwarz strain) had been administered during the first year of life. Other vaccines had also been given as routinely in France. Four months before hospitalization, she had a history of fever, cough, coryza, conjunctivitis occurring within 14 days of an ELISA
∗ Corresponding author at: Department of Infectious Diseases, Caen University Hospital, Avenue de la Côte de Nacre, 14033 Caen Cedex 9, France. E-mail address: [email protected] (A. Baldolli). http://dx.doi.org/10.1016/j.jcv.2016.05.016 1386-6532/© 2016 Elsevier B.V. All rights reserved.
confirmed exposure to measles in her sister and nephew. No rash was noted at this time. Fifteen days before hospitalization, she had visual hallucinations and aphasia. At admission, physical examination and magnetic resonance imaging (MRI) were normal. On day 10 (day 1 being the first day of hospitalization), she developed a right lateral hemianopsia, Broca’s aphasia, horizontal nystagmus and cerebellar ataxia. C-reactive protein, liver blood tests and immunologic blood results (including antineutrophil cytoplasmic antibodies) were within normal limits. Blood cell count was normal except lymphopenia (500/mm3) related to immunosuppressive therapy. Creatinin plasma level was 160 micromol/due to polyangiitis. Cerebrospinal fluid (CSF), withdrawn on day 11, revealed 1 white cell/mm3 without erythrocyte, glucose and protein were normal. Bacterial, mycobacterial and fungal cultures were negative. PCR assays for herpes simplex virus (HSV1 and 2) (Argene® ), varicella-zoster virus (Argene® ), human herpesvirus 6 (multiplex real-time PCR, Cepheid® ), Epstein-Barr virus (Argene® ), cytomegalovirus (real time PCR Roche® ), BK and JC papovavirus (multiplex real-time PCR, Cepheid® ), enterovirus, Tropheryma whipplei, rubella and measles (multiplex real-time PCR, Cepheid® ) virus were negative in CSF. Measles-specific IgG and IgM antibodies (ELISA, Microimmune Ltd® ) were detected in the serum. Electroencephalography demonstrated slow and spike waves. MRI showed an area of abnormal intensity in the left parietal and
44
A. Baldolli et al. / Journal of Clinical Virology 81 (2016) 43–46
Fig. 1. Axial brain magnetic resonance imaging T2 FLAIR images showing several hyperintensity patchy signals in the left parietal and occipital lobes, predominantly in the gray matter.
occipital lobes (Fig. 1). A presumptive diagnosis of sub-acute measles encephalitis or measles inclusion body encephalitis (MIBE) was made and the patient was treated with intravenous ribavirin. On day 12, her neurological status deteriorated with coma focal seizures; she was additionally given acyclovir. On day 15, corticosteroids were added and brain biopsy was performed on day 19. Unfortunately, due to inadequate procedure, the biopsy tissue was altered and no microscopic examination was possible. Studies of the brain tissue performed at the National Reference Laboratory for Measles and Paramyxoviridae detected virus measles RNA by RT-PCR as previously described [1]. Sequencing was used to identify 456 nucleotides of the C region of the N gene and determine the genotype as recommended by the World Health Organization. The patient’s strain belonged to D4 cluster, as shown in the phylogenetic tree (Fig. 2). Corticosteroids and acyclovir were stopped. Despite ribavirin and anticonvulsive treatment, the patient’s neurologic status continued to deteriorate and she died at day 28. 3. Other similar and contrasting cases in the literature During 2008–2011, France experienced a measles outbreak of more than 22,000 cases, of whom 52% were >15 years of age, and 5000 cases led to hospitalization [2]. Reported complications included pneumonia (6.2% of all cases), acute otitis media (1.4%), hepatitis or pancreatitis (1.1%), neurologic complications (0,12%). Neurologic complications were: myelitis (1 case), acute disseminated encephalomyelitis (25 cases) and the present case which was not described. Based on the complete nucleoprotein (N) gene sequencing, the genotype of the patient’s strain was shown to belong to the D4 cluster. It must be emphasized that this is consistent with the biological and epidemiological studies of the French 2008–2011 outbreak. Measles virus may cause 4 major CNS syndromes: 1) encephalitis or myelitis occurring during acute systemic measles infection, 2) acute disseminated measles encephalomyelitis presenting during the recovery phase of measles infection, 3) sub-acute measles encephalitis, referred to as MIBE, occurs mainly in immunocompromised patients within 1 year of measles infection or vaccination, and 4) sub-acute sclerosing panencephalitis (SSPE) presents after a latent period of a few years [3–6]. There are about 60 reported cases of MIBE [5,7,8]. MIBE occurs mainly in young immunocompromised people, such as those with: acute lymphoblastic leukaemia, HIV infection, stem cell or solid organ transplantation and autoimmune disease [3–5,9]. Clinical presentation includes afebrile focal seizures (97% of cases), partial epilepsy (78%), hemiplegia (36%), ataxia (24%), aphasia (21%) and altered mentation (100%) [3–5,9]. Seizures become refractory to anticonvulsant therapy in 36% of cases [3,5]. Exanthema is frequently absent because of poor T cell functions [3]. CSF is often normal at the beginning of the disease,
although mild pleocytosis and an elevated protein level may be observed. Measles virus antibodies in CSF are detectable in half of cases [5]. Although not specific, imaging studies may show cerebral oedema, atrophy, ventricular dilatation. Diagnosis requires brain biopsy demonstrating: neuronal loss, proliferation of astrocytes and microglia, focal necrosis, perivascular inflammation, intranuclear or intracytoplasmic inclusions. Molecular detection of measles virus has supplanted viral culture [3,5,6]. Although brain biopsy pathological study could not be done, several characteristics strongly support MIBE diagnosis: immunocompromised host, time course within one year and evidence of persistent measles infection (positive PCR on brain tissue, IgM and IgG positive antibodies). It must be emphasized that the interest of PCR detection of measles virus in the CSF remains unclear. Therefore, in case of negative results, the diagnosis of MIBE must not be ruled out and brain biopsy must be performed. MIBE prognosis is poor with mortality rates reaching 76% and neurological sequelae in all survivors [5,6]. No effective treatment is available. Immunosuppressive agents should be stopped whenever possible. Based on rare published experience, intravenous ribavirin was started. Symptoms and imaging may improve under ribavirin treatment, as seen in few cases [5,7]. Some patients have been treated with interferon-␣ without efficacy [4,5,7]. Our patient did not show any improvement during ribavirin therapy. This may be related in part to the late initiation of therapy or to the corticoid therapy, which was first administered before the diagnosis of MIBE was confirmed.
4. Discussion A two dose MMR vaccination schedule is necessary to provide measles immunity at the individual level and herd immunity at the population level. Our patient never had the second dose of MMR. When microscopic polyangiitis was diagnosed, the immunosuppressive therapy was considered urgent, and measles vaccination was not done. In France, at the beginning of 2008–2011 outbreak, the measles vaccine coverage for the second dose did not reach the 95% coverage needed to get herd immunity [2]. Therefore, these 2 factors (i.e., absence of a second injection and limited herd immunity against measles) clearly contributed to the development of measles in our immunocompromised patient. Immunization is certainly the best way to achieve herd immunity in the population. However, physicians caring for immunocompromised patients should update the vaccination schedule before starting immunosuppressive treatments whenever possible. Although severe neurological disease has been described after measles vaccination, this vaccine has been used in patients with various causes of immunosuppression [3]. The limited risk of serious adverse events following measles vaccination in the immunocompromised must be balanced against the evidence supporting the efficacy of the vaccine in reducing the morbidity and mortality associated with measles [2]. Finally, it should be emphasized that any immunocompromised patient, even vaccinated against measles, should be considered for polyvalent human immunoglobulin (PHI) treatment within 6 days following the exposure [10]. MIBE is a rare complication of measles, mainly observed in the immunocompromised host, with a high rate of mortality. Brain biopsy allows pathological diagnosis and PCR detection of measles virus. Vaccination of the whole population (herd immunity) and each individual (before being immunocompromised whenever possible) are the cornerstone of prophylaxis. In case of exposure to measles, PHI should be started within 6 days.
A. Baldolli et al. / Journal of Clinical Virology 81 (2016) 43–46
45
Fig. 2. Evolutionary relationships of 44 taxa. The evolutionary history was inferred using the Neighbor-Joining method. The percentage of replicate trees in which the associated taxa clustered together in the bootstrap test (1000 replicates) are shown next to the branches. The tree is drawn to scale, with branch lengths in the same units as those of the evolutionary distances used to infer the phylogenetic tree. The evolutionary distances were computed using the Kimura 2-parameter method and are in the units of the number of base substitutions per site. There were a total of 456 positions in the final dataset. Phylogenetic analyses were conducted in MEGA4. The strain of our patient (MVs/Caen.FRA/34.10(D4)4022brain) is in the cluster D4.
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A. Baldolli et al. / Journal of Clinical Virology 81 (2016) 43–46
Funding National Reference Laboratory for Measles. Competing interests None. Ethical approval Not applicable. References [1] J.M. Hubschen, J.R. Kremer, S. De Landtsheer, C.P. Muller, A multiplex TaqMan PCR assay for the detection of measles and rubella virus, J. Virol. Methods 149 (2) (2008) 246–250. [2] D. Antona, D. Levy-Bruhl, C. Baudon, F. Freymuth, M. Lamy, C. Maine, et al., Measles elimination efforts and 2008–2011 outbreak, France, Emerg. Infect. Dis. 19 (3) (2013) 357–364. [3] R. Buchanan, D.J. Bonthius, Measles virus and associated central nervous system sequelae, Semin. Pediatr. Neurol. 19 (3) (2012) 107–114.
[4] A.F. Freeman, D.A. Jacobsohn, S.T. Shulman, W.J. Bellini, P. Jaggi, G. de Leon, et al., A new complication of stem cell transplantation: measles inclusion body encephalitis, Pediatrics 114 (5) (2004) e657–60. [5] M.M. Mustafa, S.D. Weitman, N.J. Winick, W.J. Bellini, C.F. Timmons, J.D. Siegel, Subacute measles encephalitis in the young immunocompromised host: report of two cases diagnosed by polymerase chain reaction and treated with ribavirin and review of the literature, Clin. Infect. Dis. 16 (5) (1993) 654–660. [6] D.L. Fisher, S. Defres, T. Solomon, Measles-induced encephalitis, QJM 108 (3) (2015) 177–182. [7] I. Hughes, M.E. Jenney, R.W. Newton, D.J. Morris, P.E. Klapper, Measles encephalitis during immunosuppressive treatment for acute lymphoblastic leukaemia, Arch. Dis. Child. 68 (6) (1993) 775–778. [8] D.R. Hardie, C. Albertyn, J.M. Heckmann, H.E. Smuts, Molecular characterisation of virus in the brains of patients with measles inclusion body encephalitis (MIBE), Virol. J. 10 (2013) 283. [9] C. Albertyn, H. van der Plas, D. Hardie, S. Candy, T. Tomoka, E.B. Leepan, et al., Silent casualties from the measles outbreak in South Africa, S. Afr. Med. J. 101 (5) (2011), 313–4, 6–7. [10] H.Q. Mclean, A.P. Fiebelkorn, J.L. Temte, G.S. Wallace, Centers for Disease C, Prevention. Prevention of measles, rubella, congenital rubella syndrome, and mumps, 2013: summary recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recommendations and reports: Morbidity and mortality weekly report Recommendations and reports/Centers for Disease Control. 62 (RR-04) (2013) 1–34.
Contents lists available at ScienceDirect
Journal of Clinical Virology journal homepage: www.elsevier.com/locate/jcv
Case report
Measles inclusion-body encephalitis (MIBE) in a immunocompromised patient Aurélie Baldolli a,∗ , Sylvie Dargère a , Erick Cardineau b , Astrid Vabret c , Julia Dina c , Arnaud de La Blanchardière a , Renaud Verdon a a
Department of Infectious Diseases, University Hospital of Caen, France Department of Nephrology, Hospital of Alenc¸on-Mamers, France c Department of Virology, French National Reference Laboratory for Measles, University Hospital of Caen, France b
a r t i c l e
i n f o
Article history: Received 11 April 2016 Received in revised form 26 May 2016 Accepted 30 May 2016 Keywords: Measles Inclusion-body encephalitis Microscopic polyangiitis
1. Why this case is important Although measles immunization programs are present in Europe, several countries reported outbreaks since 2006–2007. Our case emphasizes the dramatic consequences of suboptimal adherence to these programs.
2. Case report A 27-year-old teacher was hospitalized in 2010 in Caen, France, for decrease of visual acuity with evolution towards blindness. Her medical history was marked by a microscopic polyangiitis diagnosed in 2007 which was treated with mycophenolate mofetil plus prednisone since 2009. Only one dose of measles-rubella vaccine (Rudi-Rouvax® Schwarz strain) had been administered during the first year of life. Other vaccines had also been given as routinely in France. Four months before hospitalization, she had a history of fever, cough, coryza, conjunctivitis occurring within 14 days of an ELISA
∗ Corresponding author at: Department of Infectious Diseases, Caen University Hospital, Avenue de la Côte de Nacre, 14033 Caen Cedex 9, France. E-mail address: [email protected] (A. Baldolli). http://dx.doi.org/10.1016/j.jcv.2016.05.016 1386-6532/© 2016 Elsevier B.V. All rights reserved.
confirmed exposure to measles in her sister and nephew. No rash was noted at this time. Fifteen days before hospitalization, she had visual hallucinations and aphasia. At admission, physical examination and magnetic resonance imaging (MRI) were normal. On day 10 (day 1 being the first day of hospitalization), she developed a right lateral hemianopsia, Broca’s aphasia, horizontal nystagmus and cerebellar ataxia. C-reactive protein, liver blood tests and immunologic blood results (including antineutrophil cytoplasmic antibodies) were within normal limits. Blood cell count was normal except lymphopenia (500/mm3) related to immunosuppressive therapy. Creatinin plasma level was 160 micromol/due to polyangiitis. Cerebrospinal fluid (CSF), withdrawn on day 11, revealed 1 white cell/mm3 without erythrocyte, glucose and protein were normal. Bacterial, mycobacterial and fungal cultures were negative. PCR assays for herpes simplex virus (HSV1 and 2) (Argene® ), varicella-zoster virus (Argene® ), human herpesvirus 6 (multiplex real-time PCR, Cepheid® ), Epstein-Barr virus (Argene® ), cytomegalovirus (real time PCR Roche® ), BK and JC papovavirus (multiplex real-time PCR, Cepheid® ), enterovirus, Tropheryma whipplei, rubella and measles (multiplex real-time PCR, Cepheid® ) virus were negative in CSF. Measles-specific IgG and IgM antibodies (ELISA, Microimmune Ltd® ) were detected in the serum. Electroencephalography demonstrated slow and spike waves. MRI showed an area of abnormal intensity in the left parietal and
44
A. Baldolli et al. / Journal of Clinical Virology 81 (2016) 43–46
Fig. 1. Axial brain magnetic resonance imaging T2 FLAIR images showing several hyperintensity patchy signals in the left parietal and occipital lobes, predominantly in the gray matter.
occipital lobes (Fig. 1). A presumptive diagnosis of sub-acute measles encephalitis or measles inclusion body encephalitis (MIBE) was made and the patient was treated with intravenous ribavirin. On day 12, her neurological status deteriorated with coma focal seizures; she was additionally given acyclovir. On day 15, corticosteroids were added and brain biopsy was performed on day 19. Unfortunately, due to inadequate procedure, the biopsy tissue was altered and no microscopic examination was possible. Studies of the brain tissue performed at the National Reference Laboratory for Measles and Paramyxoviridae detected virus measles RNA by RT-PCR as previously described [1]. Sequencing was used to identify 456 nucleotides of the C region of the N gene and determine the genotype as recommended by the World Health Organization. The patient’s strain belonged to D4 cluster, as shown in the phylogenetic tree (Fig. 2). Corticosteroids and acyclovir were stopped. Despite ribavirin and anticonvulsive treatment, the patient’s neurologic status continued to deteriorate and she died at day 28. 3. Other similar and contrasting cases in the literature During 2008–2011, France experienced a measles outbreak of more than 22,000 cases, of whom 52% were >15 years of age, and 5000 cases led to hospitalization [2]. Reported complications included pneumonia (6.2% of all cases), acute otitis media (1.4%), hepatitis or pancreatitis (1.1%), neurologic complications (0,12%). Neurologic complications were: myelitis (1 case), acute disseminated encephalomyelitis (25 cases) and the present case which was not described. Based on the complete nucleoprotein (N) gene sequencing, the genotype of the patient’s strain was shown to belong to the D4 cluster. It must be emphasized that this is consistent with the biological and epidemiological studies of the French 2008–2011 outbreak. Measles virus may cause 4 major CNS syndromes: 1) encephalitis or myelitis occurring during acute systemic measles infection, 2) acute disseminated measles encephalomyelitis presenting during the recovery phase of measles infection, 3) sub-acute measles encephalitis, referred to as MIBE, occurs mainly in immunocompromised patients within 1 year of measles infection or vaccination, and 4) sub-acute sclerosing panencephalitis (SSPE) presents after a latent period of a few years [3–6]. There are about 60 reported cases of MIBE [5,7,8]. MIBE occurs mainly in young immunocompromised people, such as those with: acute lymphoblastic leukaemia, HIV infection, stem cell or solid organ transplantation and autoimmune disease [3–5,9]. Clinical presentation includes afebrile focal seizures (97% of cases), partial epilepsy (78%), hemiplegia (36%), ataxia (24%), aphasia (21%) and altered mentation (100%) [3–5,9]. Seizures become refractory to anticonvulsant therapy in 36% of cases [3,5]. Exanthema is frequently absent because of poor T cell functions [3]. CSF is often normal at the beginning of the disease,
although mild pleocytosis and an elevated protein level may be observed. Measles virus antibodies in CSF are detectable in half of cases [5]. Although not specific, imaging studies may show cerebral oedema, atrophy, ventricular dilatation. Diagnosis requires brain biopsy demonstrating: neuronal loss, proliferation of astrocytes and microglia, focal necrosis, perivascular inflammation, intranuclear or intracytoplasmic inclusions. Molecular detection of measles virus has supplanted viral culture [3,5,6]. Although brain biopsy pathological study could not be done, several characteristics strongly support MIBE diagnosis: immunocompromised host, time course within one year and evidence of persistent measles infection (positive PCR on brain tissue, IgM and IgG positive antibodies). It must be emphasized that the interest of PCR detection of measles virus in the CSF remains unclear. Therefore, in case of negative results, the diagnosis of MIBE must not be ruled out and brain biopsy must be performed. MIBE prognosis is poor with mortality rates reaching 76% and neurological sequelae in all survivors [5,6]. No effective treatment is available. Immunosuppressive agents should be stopped whenever possible. Based on rare published experience, intravenous ribavirin was started. Symptoms and imaging may improve under ribavirin treatment, as seen in few cases [5,7]. Some patients have been treated with interferon-␣ without efficacy [4,5,7]. Our patient did not show any improvement during ribavirin therapy. This may be related in part to the late initiation of therapy or to the corticoid therapy, which was first administered before the diagnosis of MIBE was confirmed.
4. Discussion A two dose MMR vaccination schedule is necessary to provide measles immunity at the individual level and herd immunity at the population level. Our patient never had the second dose of MMR. When microscopic polyangiitis was diagnosed, the immunosuppressive therapy was considered urgent, and measles vaccination was not done. In France, at the beginning of 2008–2011 outbreak, the measles vaccine coverage for the second dose did not reach the 95% coverage needed to get herd immunity [2]. Therefore, these 2 factors (i.e., absence of a second injection and limited herd immunity against measles) clearly contributed to the development of measles in our immunocompromised patient. Immunization is certainly the best way to achieve herd immunity in the population. However, physicians caring for immunocompromised patients should update the vaccination schedule before starting immunosuppressive treatments whenever possible. Although severe neurological disease has been described after measles vaccination, this vaccine has been used in patients with various causes of immunosuppression [3]. The limited risk of serious adverse events following measles vaccination in the immunocompromised must be balanced against the evidence supporting the efficacy of the vaccine in reducing the morbidity and mortality associated with measles [2]. Finally, it should be emphasized that any immunocompromised patient, even vaccinated against measles, should be considered for polyvalent human immunoglobulin (PHI) treatment within 6 days following the exposure [10]. MIBE is a rare complication of measles, mainly observed in the immunocompromised host, with a high rate of mortality. Brain biopsy allows pathological diagnosis and PCR detection of measles virus. Vaccination of the whole population (herd immunity) and each individual (before being immunocompromised whenever possible) are the cornerstone of prophylaxis. In case of exposure to measles, PHI should be started within 6 days.
A. Baldolli et al. / Journal of Clinical Virology 81 (2016) 43–46
45
Fig. 2. Evolutionary relationships of 44 taxa. The evolutionary history was inferred using the Neighbor-Joining method. The percentage of replicate trees in which the associated taxa clustered together in the bootstrap test (1000 replicates) are shown next to the branches. The tree is drawn to scale, with branch lengths in the same units as those of the evolutionary distances used to infer the phylogenetic tree. The evolutionary distances were computed using the Kimura 2-parameter method and are in the units of the number of base substitutions per site. There were a total of 456 positions in the final dataset. Phylogenetic analyses were conducted in MEGA4. The strain of our patient (MVs/Caen.FRA/34.10(D4)4022brain) is in the cluster D4.
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A. Baldolli et al. / Journal of Clinical Virology 81 (2016) 43–46
Funding National Reference Laboratory for Measles. Competing interests None. Ethical approval Not applicable. References [1] J.M. Hubschen, J.R. Kremer, S. De Landtsheer, C.P. Muller, A multiplex TaqMan PCR assay for the detection of measles and rubella virus, J. Virol. Methods 149 (2) (2008) 246–250. [2] D. Antona, D. Levy-Bruhl, C. Baudon, F. Freymuth, M. Lamy, C. Maine, et al., Measles elimination efforts and 2008–2011 outbreak, France, Emerg. Infect. Dis. 19 (3) (2013) 357–364. [3] R. Buchanan, D.J. Bonthius, Measles virus and associated central nervous system sequelae, Semin. Pediatr. Neurol. 19 (3) (2012) 107–114.
[4] A.F. Freeman, D.A. Jacobsohn, S.T. Shulman, W.J. Bellini, P. Jaggi, G. de Leon, et al., A new complication of stem cell transplantation: measles inclusion body encephalitis, Pediatrics 114 (5) (2004) e657–60. [5] M.M. Mustafa, S.D. Weitman, N.J. Winick, W.J. Bellini, C.F. Timmons, J.D. Siegel, Subacute measles encephalitis in the young immunocompromised host: report of two cases diagnosed by polymerase chain reaction and treated with ribavirin and review of the literature, Clin. Infect. Dis. 16 (5) (1993) 654–660. [6] D.L. Fisher, S. Defres, T. Solomon, Measles-induced encephalitis, QJM 108 (3) (2015) 177–182. [7] I. Hughes, M.E. Jenney, R.W. Newton, D.J. Morris, P.E. Klapper, Measles encephalitis during immunosuppressive treatment for acute lymphoblastic leukaemia, Arch. Dis. Child. 68 (6) (1993) 775–778. [8] D.R. Hardie, C. Albertyn, J.M. Heckmann, H.E. Smuts, Molecular characterisation of virus in the brains of patients with measles inclusion body encephalitis (MIBE), Virol. J. 10 (2013) 283. [9] C. Albertyn, H. van der Plas, D. Hardie, S. Candy, T. Tomoka, E.B. Leepan, et al., Silent casualties from the measles outbreak in South Africa, S. Afr. Med. J. 101 (5) (2011), 313–4, 6–7. [10] H.Q. Mclean, A.P. Fiebelkorn, J.L. Temte, G.S. Wallace, Centers for Disease C, Prevention. Prevention of measles, rubella, congenital rubella syndrome, and mumps, 2013: summary recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recommendations and reports: Morbidity and mortality weekly report Recommendations and reports/Centers for Disease Control. 62 (RR-04) (2013) 1–34.