J. Neurovirol. DOI 10.1007/s13365-015-0336-0
CASE REPORT
Adult-onset subacute sclerosing panencephalitis manifesting as slowly progressive dementia Adalberto Studart Neto & Paulo Ribeiro Nóbrega & Maria Irma Seixas Duarte & Leandro Tavares Lucato & Luiz Henrique Martins Castro & Ricardo Nitrini
Received: 1 December 2014 / Revised: 13 February 2015 / Accepted: 25 February 2015 # Journal of NeuroVirology, Inc. 2015
Introduction Subacute sclerosing panencephalitis (SSPE) is a rare inflammatory and neurodegenerative disease caused by persistent brain infection with the measles virus (Singer et al. 1997; Gagnon and Bouchard 2003). SSPE is characterized by behavioral changes and mental deterioration, followed by myoclonic jerks, corticospinal signs, rigidity, frequently evolving to akinetic mutism. Death ensues in 1 to 3 years (Gutierrez et al. 2010; Garg 2008). Diagnosis is established by the characteristic clinical picture, intrathecal anti-measles antibody production, typical electroencephalographic, and brain histopathologic findings (Garg 2008; Eroglu et al. 2008). Neuropathology is characterized by parenchymal inflammatory infiltrates, demyelination, A. Studart Neto (*) : P. R. Nóbrega : L. H. M. Castro : R. Nitrini Department of Neurology, Faculdade de Medicina, Universidade de São Paulo, Av. Dr. Enéas de Carvalho Aguiar, 255, Cerqueira César, São Paulo, SP 05403-000, Brazil e-mail: [email protected] P. R. Nóbrega e-mail: [email protected] L. H. M. Castro e-mail: [email protected] R. Nitrini e-mail: [email protected] M. I. S. Duarte Department of Pathology, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil e-mail: [email protected] L. T. Lucato Department of Radiology, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil e-mail: [email protected]
and neuronal, olygodendrocytic, and astrocytic viral inclusions, neuronal degeneration, and astrogliosis (Garg 2008). SSPE primarily affects children. Adult-onset SSPE is rare and often presents with atypical features (Fabian et al. 2010). We report the case of a 50-year-old man with slowly progressive dementia secondary to histologically confirmed SSPE.
Case report A 50-year-old male police officer, with 9 years of education, presented with an 8-year history of behavioral changes, initially treated as psychiatric disease. After 3 years, he presented difficulty recalling recent events and later developed uncontrollable hiccups. There was no history of measles or immunization. Neurological examination was remarkable for impaired attention, executive functions and working memory, decreased phonemic and semantic verbal fluency, a Mini-Mental State Examination Score of 19/30, frontal release signs, motor perseveration, and a palmar grasping reflex. Myoclonus or other movement disorders were not observed. Visual fields and funduscopic exam were normal. Brain MRI showed bilaterally symmetrical confluent noncontrast-enhancing T2-weighted/FLAIR hyperintense lesions involving subcortical, deep hemispheric, and pontine white matter (Fig. 1a–c). CSF exam revealed 32 leukocytes (21 % neutrophils, 68 % lymphocytes, and 13 % mononuclear cells), a protein of 117 mg/dl and glucose of 54 mg/dl, with increased gammaglobulin levels on protein electrophoresis (36 %; normal up to 14 %). Oligoclonal bands and IgG testing were not performed. Polymerase chain reaction (PCR) for adenovirus, cytomegalovirus, and herpes simplex viruses, as well as syphilis antibodies resulted negative. PCR for measles,
J. Neurovirol. Fig. 1 Initial (a–c) and follow-up (17 months after the initial one) (d–f) brain MRI. FLAIR images from the initial exam (a–c): confluent bilateral and symmetric hyperintensities involving subcortical and deep white matter of the cerebral hemispheres and pons. Follow-up FLAIR images (d, e): more extensive signal changes, involving the middle cerebellar peduncles (arrows in d) and thalami (arrows in e). Followup diffusion-weighted images (f) show no diffusion restriction
varicella-zoster, and JC viruses, as well as measles antibodies were not performed at that moment. EEG showed diffuse background slowing, without periodic activity. Extensive evaluation for systemic diseases resulted negative. A right frontal lobe biopsy was obtained that showed mild pericapillary and arteriolar lymphocytic infiltrates. A diagnosis of primary central nervous system angiitis was entertained, and the patient was treated with two monthly intravenous 5 g methylprednisolone and 1 g cyclophosphamide courses. Thereafter, cognitive status rapidly deteriorated. The patient became dependent for daily living activities. Two months later, he became unresponsive and was readmitted to the hospital. The patient was unable to obey simple commands. A repeat CSF exam showed five leukocytes (43 % neutrophils, 54 % lymphocytes, and 3 % mononuclear cells), a protein of 159 mg/dl, glucose of 62 mg/dl, and 34 % gammaglobulin levels. CSF and serum PCR for herpes simplex, cytomegalovirus, varicella-zoster, and JC viruses resulted negative. CSF IgG antibodies to measles were positive, while serum antibodies were negative. Patient’s CSF was not tested by reverse transcriptase PCR for viral RNA expression. Follow-up MRI (17 months after the initial one) disclosed more extensive signal changes, now involving thalami, middle cerebellar peduncles, and deep hemispheric cerebellar white matter (Fig. 1d–f). The patient underwent a repeat cerebral biopsy, targeting the right thalamus. Histopathology showed diffuse brain parenchymal inflammatory and neurodegenerative changes, with edema and
neuronal loss (Fig. 2a–c), scant lymphocytic infiltrates, along with plasma cells and macrophages, grouped into microglial nodules, particularly in perivascular regions, as well as vasculitic changes and gliosis with reactive astro- and oligodendrocyte proliferation. Rare viral inclusions were noted in neuronal, astrocyte, and oligodendrocyte nuclei that were enlarged and hyperchromatic (Fig. 2g–i). A streptavidin-biotin peroxidase immunohistochemical method was performed with LSAB® + kit (LSAB + KIT, K0690, Dako Corporation, Carpinteria, CA, USA). The primary antibody anti-measles (MAB8905, Chemicon, USA) was applied, and after an overnight incubation at 4 °C, it was applied the second antibody. Immune staining for measles was positive in neuronal, astrocyte, oligodendrocyte, and lymphocyte nuclei, in a granular pattern (Figs. 2e, f and 3). Direct reverse transcriptasepolymerase chain reaction (RT-PCR) for viral RNA in brain tissue was not performed. Results were consistent with subacute sclerosing panencephalitis. After 15 months, the patient was in a vegetative state.
Discussion Adult-onset SSPE has been reported. Incidence ranges from 0.01 per million in the USA to 21 per million in India (Gutierrez et al. 2010). Among 307 SSPE patients evaluated
J. Neurovirol.
Fig. 2 Subacute sclerosing panencephalitis. a Panoramic view showing increased cellularity and perivascular inflammatory infiltrates. HE ×40. b Oligodendrocyte proliferation, astrocyte reactivity, and vasculitis and lymphocyte perivascular cuffing (detail). HE ×100. c Microglial nodule. HE ×200. d Inclusion body in oligodendrocyte nuclei. HE ×400. e, f Positive immunostaining for measles antigen in oligodendrocytes,
astrocytes, lymphocytes, and neurons. Inset: immunostaining in neuron. g, h Ultrastructural aspect of viral nucleocapsids increasing oligodendrocyte nuclear volume, replacing the original chromatin (bar 1 μm, 0.5 μm). e Nuclear inclusions and granulous filaments in oligodendrocyte nuclei (bar: 5 μm)
retrospectively over 10 years in India, 39 cases (12.7 %) presented after 18 years of age (Prashanth et al. 2006). Mean onset age was 20.9 years (range 18–43 years) (Prashanth et al. 2006). No differences were found comparing adult and pediatric onset cases, except for the interval between measles infection and symptom onset. Adult-onset cases show higher proportion of negative/ undocumented measles exposure. Our patient probably did not receive measles vaccine, since vaccination coverage in Brazil was low until the 1980s. No etiological relationship
between measles vaccine and SSPE has been established. No vaccine-related adult-onset SSPE cases have been reported (Gutierrez et al. 2010; Prashanth et al. 2006). Interval between initial symptoms and vegetative state was 8 years in our patient. In a case series, only 20 % SSPE patients survived more than 4 years (Singer et al. 1997). Our case manifested with behavioral and cognitive changes without myoclonus or EEG periodic activity, a finding also noted in adult-onset SSPE without myoclonus (González de la Aleja J et al. 2005; Ortega-Aznar et al. 2003). Brain MRI showed diffuse white-matter disease with brain atrophy. Diffuse demyelinating leukoencephalopathy has been reported (Vilas et al. 2012; Ortega-Aznar et al. 2003). Mild CSF pleocytosis with elevated protein and (Gutierrez et al. 2010; Croxson et al. 2002) increased CSF gammaglobulin levels are well-recognized in SSPE. CSF IgG measles antibodies display a 100 % sensitivity, 93.3 % specificity with 100 % positive predictive value in SSPE (Garg 2008; Gutierrez et al. 2010). While measles-specific PCR can result negative in the CSF, (Croxson et al. 2002; Vilas et al. 2012) RT-PCR viral RNA reliably detects measles virus strains in brain tissue. Impaired immune cellular response, as well as wild-type viral mutations may play a role in SSPE pathogenesis, resulting in persistent measles infection in brain neurons, corroborated by RT-PCR (Garg 2008).
Fig. 3 Subacute sclerosing panencephalitis: immunohistochemical showing neuronal, oligodendrocyte, astrocyte, and lymphocyte positivity for measles antigens. Original magnification ×400
J. Neurovirol.
Histological findings in this case were similar to other cases, including extensive demyelination, perivascular inflammation, neuronal degeneration, intracellular inclusions (Singer et al. 1997; Ortega-Aznar et al. 2003), and astrogliosis. There is no effective treatment for SSPE. Thirty to thirtyfive percent of cases show modest benefit from therapy, with slow disease progression and unchanged 95 % mortality rate. Isoprinosine, combined or not with intrathecal interferon alpha are drugs of choice (Gutierrez et al. 2010). Our patient was not treated due to advanced disease stage. The diagnosis of adult-onset SSPE may be challenging and should be suspected when high CSF gammaglobulin levels are noted, accompanied or not by CSF pleocytosis, after excluding more common causes of slowly progressive dementia. Acknowledgments We thank Dr. Bruno Fukelmann Guedes for logistical support in formatting the figure of this manuscript. Conflict of interest The authors declare no conflicts of interest and financial disclosures.
References Croxson MC, Anderson NE, Vaughan AA et al (2002) Subacute measles encephalitis in an immunocompetent adult. J Clin Neurosci 9(5): 600–604
Eroglu E, Gokcil Z, Bek S et al (2008) Long-term follow-up of patients with adult-onset subacute sclerosing panencephalitis. J Neurol Sci 275:113–116 Fabian VA, Lee HY, Keith-Rokosh JL et al (2010) A 22-year-old Australian woman with atypical subacute sclerosing panencephalitis diagnosed at postmortem. J Clin Neurosci 17: 1192–1194 Gagnon A, Bouchard RW (2003) Fulminating adult-onset subacute sclerosing panencephalitis in a 49-year-old man. Arch Neurol 60:1160– 1161 Garg RK (2008) Subacute sclerosing panencephalitis. J Neurol 255: 1861–1871 González de la Aleja J, Posada IJ, Sepúlveda-Sánchez JM et al (2005) Adult-onset subacute sclerosing panencephalitis: clinicopathological findings. Rev Neurol 40(12):729–732 Gutierrez J, Issacson RS, Koppel BS (2010) Subacute sclerosing panencephalitis: an update. Dev Med Child Neurol 52:901– 907 Ortega-Aznar A, Romero-Vidal FJ, Castellví J et al (2003) Adult-onset subacute sclerosing panencephalitis: clinicopathological findings in 2 new cases. Clin Neuropathol 22(3):110–118 Prashanth LK, Taly AB, Ravi V et al (2006) Adult onset subacute sclerosing panencephalitis: clinical profile of 39 patients from a tertiary care centre. J Neurol Neurosurg Psychiatry 77:630– 633 Singer C, Lang A, Suchowersky O (1997) Adult-onset subacute sclerosing panencephalitis: case reports and review of the literature. Mov Disord 12:342–353 Vilas D, Becerra JL, Lozano M et al (2012) Atypical presentation of adult-age onset subacute sclerosing panencephalitis. Rev Neurol 54:60–61
CASE REPORT
Adult-onset subacute sclerosing panencephalitis manifesting as slowly progressive dementia Adalberto Studart Neto & Paulo Ribeiro Nóbrega & Maria Irma Seixas Duarte & Leandro Tavares Lucato & Luiz Henrique Martins Castro & Ricardo Nitrini
Received: 1 December 2014 / Revised: 13 February 2015 / Accepted: 25 February 2015 # Journal of NeuroVirology, Inc. 2015
Introduction Subacute sclerosing panencephalitis (SSPE) is a rare inflammatory and neurodegenerative disease caused by persistent brain infection with the measles virus (Singer et al. 1997; Gagnon and Bouchard 2003). SSPE is characterized by behavioral changes and mental deterioration, followed by myoclonic jerks, corticospinal signs, rigidity, frequently evolving to akinetic mutism. Death ensues in 1 to 3 years (Gutierrez et al. 2010; Garg 2008). Diagnosis is established by the characteristic clinical picture, intrathecal anti-measles antibody production, typical electroencephalographic, and brain histopathologic findings (Garg 2008; Eroglu et al. 2008). Neuropathology is characterized by parenchymal inflammatory infiltrates, demyelination, A. Studart Neto (*) : P. R. Nóbrega : L. H. M. Castro : R. Nitrini Department of Neurology, Faculdade de Medicina, Universidade de São Paulo, Av. Dr. Enéas de Carvalho Aguiar, 255, Cerqueira César, São Paulo, SP 05403-000, Brazil e-mail: [email protected] P. R. Nóbrega e-mail: [email protected] L. H. M. Castro e-mail: [email protected] R. Nitrini e-mail: [email protected] M. I. S. Duarte Department of Pathology, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil e-mail: [email protected] L. T. Lucato Department of Radiology, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil e-mail: [email protected]
and neuronal, olygodendrocytic, and astrocytic viral inclusions, neuronal degeneration, and astrogliosis (Garg 2008). SSPE primarily affects children. Adult-onset SSPE is rare and often presents with atypical features (Fabian et al. 2010). We report the case of a 50-year-old man with slowly progressive dementia secondary to histologically confirmed SSPE.
Case report A 50-year-old male police officer, with 9 years of education, presented with an 8-year history of behavioral changes, initially treated as psychiatric disease. After 3 years, he presented difficulty recalling recent events and later developed uncontrollable hiccups. There was no history of measles or immunization. Neurological examination was remarkable for impaired attention, executive functions and working memory, decreased phonemic and semantic verbal fluency, a Mini-Mental State Examination Score of 19/30, frontal release signs, motor perseveration, and a palmar grasping reflex. Myoclonus or other movement disorders were not observed. Visual fields and funduscopic exam were normal. Brain MRI showed bilaterally symmetrical confluent noncontrast-enhancing T2-weighted/FLAIR hyperintense lesions involving subcortical, deep hemispheric, and pontine white matter (Fig. 1a–c). CSF exam revealed 32 leukocytes (21 % neutrophils, 68 % lymphocytes, and 13 % mononuclear cells), a protein of 117 mg/dl and glucose of 54 mg/dl, with increased gammaglobulin levels on protein electrophoresis (36 %; normal up to 14 %). Oligoclonal bands and IgG testing were not performed. Polymerase chain reaction (PCR) for adenovirus, cytomegalovirus, and herpes simplex viruses, as well as syphilis antibodies resulted negative. PCR for measles,
J. Neurovirol. Fig. 1 Initial (a–c) and follow-up (17 months after the initial one) (d–f) brain MRI. FLAIR images from the initial exam (a–c): confluent bilateral and symmetric hyperintensities involving subcortical and deep white matter of the cerebral hemispheres and pons. Follow-up FLAIR images (d, e): more extensive signal changes, involving the middle cerebellar peduncles (arrows in d) and thalami (arrows in e). Followup diffusion-weighted images (f) show no diffusion restriction
varicella-zoster, and JC viruses, as well as measles antibodies were not performed at that moment. EEG showed diffuse background slowing, without periodic activity. Extensive evaluation for systemic diseases resulted negative. A right frontal lobe biopsy was obtained that showed mild pericapillary and arteriolar lymphocytic infiltrates. A diagnosis of primary central nervous system angiitis was entertained, and the patient was treated with two monthly intravenous 5 g methylprednisolone and 1 g cyclophosphamide courses. Thereafter, cognitive status rapidly deteriorated. The patient became dependent for daily living activities. Two months later, he became unresponsive and was readmitted to the hospital. The patient was unable to obey simple commands. A repeat CSF exam showed five leukocytes (43 % neutrophils, 54 % lymphocytes, and 3 % mononuclear cells), a protein of 159 mg/dl, glucose of 62 mg/dl, and 34 % gammaglobulin levels. CSF and serum PCR for herpes simplex, cytomegalovirus, varicella-zoster, and JC viruses resulted negative. CSF IgG antibodies to measles were positive, while serum antibodies were negative. Patient’s CSF was not tested by reverse transcriptase PCR for viral RNA expression. Follow-up MRI (17 months after the initial one) disclosed more extensive signal changes, now involving thalami, middle cerebellar peduncles, and deep hemispheric cerebellar white matter (Fig. 1d–f). The patient underwent a repeat cerebral biopsy, targeting the right thalamus. Histopathology showed diffuse brain parenchymal inflammatory and neurodegenerative changes, with edema and
neuronal loss (Fig. 2a–c), scant lymphocytic infiltrates, along with plasma cells and macrophages, grouped into microglial nodules, particularly in perivascular regions, as well as vasculitic changes and gliosis with reactive astro- and oligodendrocyte proliferation. Rare viral inclusions were noted in neuronal, astrocyte, and oligodendrocyte nuclei that were enlarged and hyperchromatic (Fig. 2g–i). A streptavidin-biotin peroxidase immunohistochemical method was performed with LSAB® + kit (LSAB + KIT, K0690, Dako Corporation, Carpinteria, CA, USA). The primary antibody anti-measles (MAB8905, Chemicon, USA) was applied, and after an overnight incubation at 4 °C, it was applied the second antibody. Immune staining for measles was positive in neuronal, astrocyte, oligodendrocyte, and lymphocyte nuclei, in a granular pattern (Figs. 2e, f and 3). Direct reverse transcriptasepolymerase chain reaction (RT-PCR) for viral RNA in brain tissue was not performed. Results were consistent with subacute sclerosing panencephalitis. After 15 months, the patient was in a vegetative state.
Discussion Adult-onset SSPE has been reported. Incidence ranges from 0.01 per million in the USA to 21 per million in India (Gutierrez et al. 2010). Among 307 SSPE patients evaluated
J. Neurovirol.
Fig. 2 Subacute sclerosing panencephalitis. a Panoramic view showing increased cellularity and perivascular inflammatory infiltrates. HE ×40. b Oligodendrocyte proliferation, astrocyte reactivity, and vasculitis and lymphocyte perivascular cuffing (detail). HE ×100. c Microglial nodule. HE ×200. d Inclusion body in oligodendrocyte nuclei. HE ×400. e, f Positive immunostaining for measles antigen in oligodendrocytes,
astrocytes, lymphocytes, and neurons. Inset: immunostaining in neuron. g, h Ultrastructural aspect of viral nucleocapsids increasing oligodendrocyte nuclear volume, replacing the original chromatin (bar 1 μm, 0.5 μm). e Nuclear inclusions and granulous filaments in oligodendrocyte nuclei (bar: 5 μm)
retrospectively over 10 years in India, 39 cases (12.7 %) presented after 18 years of age (Prashanth et al. 2006). Mean onset age was 20.9 years (range 18–43 years) (Prashanth et al. 2006). No differences were found comparing adult and pediatric onset cases, except for the interval between measles infection and symptom onset. Adult-onset cases show higher proportion of negative/ undocumented measles exposure. Our patient probably did not receive measles vaccine, since vaccination coverage in Brazil was low until the 1980s. No etiological relationship
between measles vaccine and SSPE has been established. No vaccine-related adult-onset SSPE cases have been reported (Gutierrez et al. 2010; Prashanth et al. 2006). Interval between initial symptoms and vegetative state was 8 years in our patient. In a case series, only 20 % SSPE patients survived more than 4 years (Singer et al. 1997). Our case manifested with behavioral and cognitive changes without myoclonus or EEG periodic activity, a finding also noted in adult-onset SSPE without myoclonus (González de la Aleja J et al. 2005; Ortega-Aznar et al. 2003). Brain MRI showed diffuse white-matter disease with brain atrophy. Diffuse demyelinating leukoencephalopathy has been reported (Vilas et al. 2012; Ortega-Aznar et al. 2003). Mild CSF pleocytosis with elevated protein and (Gutierrez et al. 2010; Croxson et al. 2002) increased CSF gammaglobulin levels are well-recognized in SSPE. CSF IgG measles antibodies display a 100 % sensitivity, 93.3 % specificity with 100 % positive predictive value in SSPE (Garg 2008; Gutierrez et al. 2010). While measles-specific PCR can result negative in the CSF, (Croxson et al. 2002; Vilas et al. 2012) RT-PCR viral RNA reliably detects measles virus strains in brain tissue. Impaired immune cellular response, as well as wild-type viral mutations may play a role in SSPE pathogenesis, resulting in persistent measles infection in brain neurons, corroborated by RT-PCR (Garg 2008).
Fig. 3 Subacute sclerosing panencephalitis: immunohistochemical showing neuronal, oligodendrocyte, astrocyte, and lymphocyte positivity for measles antigens. Original magnification ×400
J. Neurovirol.
Histological findings in this case were similar to other cases, including extensive demyelination, perivascular inflammation, neuronal degeneration, intracellular inclusions (Singer et al. 1997; Ortega-Aznar et al. 2003), and astrogliosis. There is no effective treatment for SSPE. Thirty to thirtyfive percent of cases show modest benefit from therapy, with slow disease progression and unchanged 95 % mortality rate. Isoprinosine, combined or not with intrathecal interferon alpha are drugs of choice (Gutierrez et al. 2010). Our patient was not treated due to advanced disease stage. The diagnosis of adult-onset SSPE may be challenging and should be suspected when high CSF gammaglobulin levels are noted, accompanied or not by CSF pleocytosis, after excluding more common causes of slowly progressive dementia. Acknowledgments We thank Dr. Bruno Fukelmann Guedes for logistical support in formatting the figure of this manuscript. Conflict of interest The authors declare no conflicts of interest and financial disclosures.
References Croxson MC, Anderson NE, Vaughan AA et al (2002) Subacute measles encephalitis in an immunocompetent adult. J Clin Neurosci 9(5): 600–604
Eroglu E, Gokcil Z, Bek S et al (2008) Long-term follow-up of patients with adult-onset subacute sclerosing panencephalitis. J Neurol Sci 275:113–116 Fabian VA, Lee HY, Keith-Rokosh JL et al (2010) A 22-year-old Australian woman with atypical subacute sclerosing panencephalitis diagnosed at postmortem. J Clin Neurosci 17: 1192–1194 Gagnon A, Bouchard RW (2003) Fulminating adult-onset subacute sclerosing panencephalitis in a 49-year-old man. Arch Neurol 60:1160– 1161 Garg RK (2008) Subacute sclerosing panencephalitis. J Neurol 255: 1861–1871 González de la Aleja J, Posada IJ, Sepúlveda-Sánchez JM et al (2005) Adult-onset subacute sclerosing panencephalitis: clinicopathological findings. Rev Neurol 40(12):729–732 Gutierrez J, Issacson RS, Koppel BS (2010) Subacute sclerosing panencephalitis: an update. Dev Med Child Neurol 52:901– 907 Ortega-Aznar A, Romero-Vidal FJ, Castellví J et al (2003) Adult-onset subacute sclerosing panencephalitis: clinicopathological findings in 2 new cases. Clin Neuropathol 22(3):110–118 Prashanth LK, Taly AB, Ravi V et al (2006) Adult onset subacute sclerosing panencephalitis: clinical profile of 39 patients from a tertiary care centre. J Neurol Neurosurg Psychiatry 77:630– 633 Singer C, Lang A, Suchowersky O (1997) Adult-onset subacute sclerosing panencephalitis: case reports and review of the literature. Mov Disord 12:342–353 Vilas D, Becerra JL, Lozano M et al (2012) Atypical presentation of adult-age onset subacute sclerosing panencephalitis. Rev Neurol 54:60–61
