Author's Accepted Manuscript
The Janus of Rasmussen’s encephalitis: Never a friendly face Elaine Wirrell MD
www.elsevier.com/locate/enganabound
PII: DOI: Reference:
S1071-9091(14)00051-5 http://dx.doi.org/10.1016/j.spen.2014.05.004 YSPEN498
To appear in: Semin Pediatr Neurol
Cite this article as: Elaine Wirrell MD, The Janus of Rasmussen’s encephalitis: Never a friendly face, Semin Pediatr Neurol , http://dx.doi.org/10.1016/j.spen.2014.05.004 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
The Janus of Rasmussen’s Encephalitis: Never a Friendly Face Elaine Wirrell MD, Professor of Neurology, Divisions of Child and Adolescent Neurology, Mayo Clinic, Rochester MN Address: 200 First St SW Rochester MN 55905 Phone (507)266‐0774 Fax (507)284‐0727 Email: [email protected]
Rasmussen’s Encephalitis (RE) is a devastating but important cause of medically intractable epilepsy in children, first described by Theodore Rasmussen in 1958 at the Montreal Neurological Institute (1). Since then, there has been progress in our understanding of the clinical evolution and pathology. However, progress in comprehending the underlying triggers, pathophysiology and effective early therapies has been disappointing. A European Consensus providing guidelines for diagnosis and treatment of RE was published in 2005 (2). RE most commonly affects children and young adults, presenting with progressive, medically intractable, focal epilepsy, which frequently progresses to epilepsia partialis continua, unihemispheric brain atrophy with contralateral hemiparesis hemianopia and cognitive decline (3). Ultimately patients enter a more stable, residual stage with severe neurological deficits and persisting, intractable seizures. While the diagnosis of RE can be made clinically, MRI provides confirmatory evidence, with most patients showing MRI changes within months of clinical onset. Characteristic imaging findings consist of unilateral ventricular enlargement, atrophy and T2 hyperintensities, which are often initially seen in the temporoinsular region but subsequently spread to the rest of the hemisphere, and ipsilateral atrophy of the caudate head (3). Gadolinium enhancement is usually absent. FDG PET can show diffuse hemispheric hypometabolism even before significant atrophy is present (3). While there are no pathognomic EEG changes that distinguish RE from other causes of focal epilepsy, high amplitude delta over the affected hemisphere, as well as epileptiform discharges, which are usually widespread over the affected hemisphere are seen. Discharges may also spread to the nonaffected hemisphere in over half of cases, but are not indicative of bilateral disease (3). The characteristic pathological features of RE include cortical inflammation, gliosis and neuronal loss which may be multifocal but remain confined to a single hemisphere (3). Microglial nodules and perivascular cuffing are frequent features. The best evidence to date suggests that at disease onset, cytotoxic T lymphocytes initiate an inflammatory process which leads to neuronal damage. Autoantigenic peptides then generate an antibody response with activation of astroglial and microglial cell populations, with neuronal and cortical injury (4‐6). The variability in clinical presentation is nicely illustrated in the article by Press et al. (7). Approximately 10% of cases begin in adolescence or adulthood and their clinical course is usually less severe, with a better response to imumunotherapy (8). Gambardella et al. described relatively non‐ progressive cases of RE beginning in adolescents and young adults which may remain circumscribed without development of a fixed neurological deficit or epilepsia partialis continua (9). Cases with
unilateral movement disorders, such as hemiathetosis and hemidystonia have also been reported, which correlate with atrophy of the caudate head (10). Bien et al. also reported a form of RE leading to progressive hemiparesis in children, either without seizures or with delayed onset of epilepsy (11). Rarely, malignant, early onset forms with bilateral involvement can be seen (12). One of the major mysteries of RE is why it remains unihemispheric? Similar to Case 2 described by Press et al. (7), approximately 10% of cases of RE have dual pathology with associated findings of focal cortical dysplasia, tuberous sclerosis, low grade tumors, vascular abnormalities or old ischemic lesions (13,14). There have also been suggestions that viral infections may result in RE, although data remain contradictory and inconclusive. These findings suggest that focal seizures may damage both neurons and the blood‐brain barrier, allowing access of antibodies as well as migration of immune cells mediating both cellular and humeral immunity. The possibility that a genetic etiology may predispose to such an immune response is enticing but requires further study. While immunomodulatory therapies may slow progression, the only definitive treatment for seizures in RE is functional hemispherectomy or hemispherotomy,. While seizure freedom rates are high after surgery, this procedure results in significant, permanent neurological deficits. Multicenter collaborative studies are needed to identify antigens associated with RE, as well as predisposing genetic or environmental factors. Such work would increase our understanding of triggers of this devastating condition and pave the way for identification of early and effective therapies which could prevent severe neurological decline and preclude the need for deficit‐causing surgery.
References: 1. Rasmussen T, Olszewski j, Lloyd‐Smith D. Focal seizures due to chronic localized encephalitis. Neurology 1958;8:435‐45. 2. Bien CG, Granata T, Antozzi C, et al. Pathogenesis, diagnosis and treatment of Rasmussen encephalitis: a European consensus statement. Brain 2005;128:454‐71. 3. Varadkar S, Bien CG, Kruse CA, et al. Rasmussen’s encephalitis: clinical features, pathobiology and treatment advances. Lancet Neurol 2014;13:195‐205. 4. Farrell MA, Droogan O, Secor DL, et al. Chronic encephalitis associated with epilepsy: immunohistochemicaland ultrasound studies. Acta Neuropathol Berl 1995;89:313‐21. 5. Li Y, Uccelli A, Laxer KD, et al. Local clonal expansion of infiltrating T lymphocytes in chronic encephalitisof Rasmussen. J Immunol 1997;158:1428‐37. 6. Bien CG, Bauer J, Deckwerth TL, et al. Destruction of neurons by cytotoxic T cells: a new pathogenic mechanism in Rasmussen’s encephalitis. Ann Neurol 2002;51:311‐18. 7. Press C, Wallace A, Chapman KE. The Janus of Rasmussens’ Encephalitis. Sem Pediatr Neurol 2014:xxxxx 8. Oguni H, Anderman F, Rasmussen TB. The natural history of the syndrome of chronic encephalitis and epilepsy: a study of the MNI series of forty eight cases. In Anderman F (ed) Chronic Encephalitis and Epilepsy: Rasmussen’s Syndrome. Boston MA, Butterworth‐ Heinemann, p 7‐35. 9. Gambardella A, Andermann F, Shorvon S, et al. Limited chronic focal encephalitis: another variant of Rasmussen syndrome. Neurology 2008;70:374‐7. 10. Frucht S. Dystonia, athetosis and epilepsia partialis continua in a patient with late‐onset Rasmussen’s encephalitis. Mov Disord 2002;17:609‐12. 11. Bien CG, Elger CE, Leitner Y et al. Slowly progressive hemiparesis in childhood as a consequence of Rasmussen encephalitis without or with delayed‐onset seizures. Eur J Neurol 2007;14:387‐90. 12. Andermann F, Farrell K. Early onset Rasmussen’s syndrome: a malignant often bilateral form of the disorder. Epilepsy Res 2006;70 (suppl): S259‐62. 13. Hart YM, Andermann F, Robitaille Y, et al. Double pathology in Rasmussen’s syndrome: a window on the etiology. Neurology 1998;50:731‐5. 14. Takai H, Wilfong A, Malphrus A, et al. Dual pathology in Rasmussen’s encephalitis: a study of seven cases and review of the literature. Neuropathology 2010;30:381‐91.
The Janus of Rasmussen’s encephalitis: Never a friendly face Elaine Wirrell MD
www.elsevier.com/locate/enganabound
PII: DOI: Reference:
S1071-9091(14)00051-5 http://dx.doi.org/10.1016/j.spen.2014.05.004 YSPEN498
To appear in: Semin Pediatr Neurol
Cite this article as: Elaine Wirrell MD, The Janus of Rasmussen’s encephalitis: Never a friendly face, Semin Pediatr Neurol , http://dx.doi.org/10.1016/j.spen.2014.05.004 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
The Janus of Rasmussen’s Encephalitis: Never a Friendly Face Elaine Wirrell MD, Professor of Neurology, Divisions of Child and Adolescent Neurology, Mayo Clinic, Rochester MN Address: 200 First St SW Rochester MN 55905 Phone (507)266‐0774 Fax (507)284‐0727 Email: [email protected]
Rasmussen’s Encephalitis (RE) is a devastating but important cause of medically intractable epilepsy in children, first described by Theodore Rasmussen in 1958 at the Montreal Neurological Institute (1). Since then, there has been progress in our understanding of the clinical evolution and pathology. However, progress in comprehending the underlying triggers, pathophysiology and effective early therapies has been disappointing. A European Consensus providing guidelines for diagnosis and treatment of RE was published in 2005 (2). RE most commonly affects children and young adults, presenting with progressive, medically intractable, focal epilepsy, which frequently progresses to epilepsia partialis continua, unihemispheric brain atrophy with contralateral hemiparesis hemianopia and cognitive decline (3). Ultimately patients enter a more stable, residual stage with severe neurological deficits and persisting, intractable seizures. While the diagnosis of RE can be made clinically, MRI provides confirmatory evidence, with most patients showing MRI changes within months of clinical onset. Characteristic imaging findings consist of unilateral ventricular enlargement, atrophy and T2 hyperintensities, which are often initially seen in the temporoinsular region but subsequently spread to the rest of the hemisphere, and ipsilateral atrophy of the caudate head (3). Gadolinium enhancement is usually absent. FDG PET can show diffuse hemispheric hypometabolism even before significant atrophy is present (3). While there are no pathognomic EEG changes that distinguish RE from other causes of focal epilepsy, high amplitude delta over the affected hemisphere, as well as epileptiform discharges, which are usually widespread over the affected hemisphere are seen. Discharges may also spread to the nonaffected hemisphere in over half of cases, but are not indicative of bilateral disease (3). The characteristic pathological features of RE include cortical inflammation, gliosis and neuronal loss which may be multifocal but remain confined to a single hemisphere (3). Microglial nodules and perivascular cuffing are frequent features. The best evidence to date suggests that at disease onset, cytotoxic T lymphocytes initiate an inflammatory process which leads to neuronal damage. Autoantigenic peptides then generate an antibody response with activation of astroglial and microglial cell populations, with neuronal and cortical injury (4‐6). The variability in clinical presentation is nicely illustrated in the article by Press et al. (7). Approximately 10% of cases begin in adolescence or adulthood and their clinical course is usually less severe, with a better response to imumunotherapy (8). Gambardella et al. described relatively non‐ progressive cases of RE beginning in adolescents and young adults which may remain circumscribed without development of a fixed neurological deficit or epilepsia partialis continua (9). Cases with
unilateral movement disorders, such as hemiathetosis and hemidystonia have also been reported, which correlate with atrophy of the caudate head (10). Bien et al. also reported a form of RE leading to progressive hemiparesis in children, either without seizures or with delayed onset of epilepsy (11). Rarely, malignant, early onset forms with bilateral involvement can be seen (12). One of the major mysteries of RE is why it remains unihemispheric? Similar to Case 2 described by Press et al. (7), approximately 10% of cases of RE have dual pathology with associated findings of focal cortical dysplasia, tuberous sclerosis, low grade tumors, vascular abnormalities or old ischemic lesions (13,14). There have also been suggestions that viral infections may result in RE, although data remain contradictory and inconclusive. These findings suggest that focal seizures may damage both neurons and the blood‐brain barrier, allowing access of antibodies as well as migration of immune cells mediating both cellular and humeral immunity. The possibility that a genetic etiology may predispose to such an immune response is enticing but requires further study. While immunomodulatory therapies may slow progression, the only definitive treatment for seizures in RE is functional hemispherectomy or hemispherotomy,. While seizure freedom rates are high after surgery, this procedure results in significant, permanent neurological deficits. Multicenter collaborative studies are needed to identify antigens associated with RE, as well as predisposing genetic or environmental factors. Such work would increase our understanding of triggers of this devastating condition and pave the way for identification of early and effective therapies which could prevent severe neurological decline and preclude the need for deficit‐causing surgery.
References: 1. Rasmussen T, Olszewski j, Lloyd‐Smith D. Focal seizures due to chronic localized encephalitis. Neurology 1958;8:435‐45. 2. Bien CG, Granata T, Antozzi C, et al. Pathogenesis, diagnosis and treatment of Rasmussen encephalitis: a European consensus statement. Brain 2005;128:454‐71. 3. Varadkar S, Bien CG, Kruse CA, et al. Rasmussen’s encephalitis: clinical features, pathobiology and treatment advances. Lancet Neurol 2014;13:195‐205. 4. Farrell MA, Droogan O, Secor DL, et al. Chronic encephalitis associated with epilepsy: immunohistochemicaland ultrasound studies. Acta Neuropathol Berl 1995;89:313‐21. 5. Li Y, Uccelli A, Laxer KD, et al. Local clonal expansion of infiltrating T lymphocytes in chronic encephalitisof Rasmussen. J Immunol 1997;158:1428‐37. 6. Bien CG, Bauer J, Deckwerth TL, et al. Destruction of neurons by cytotoxic T cells: a new pathogenic mechanism in Rasmussen’s encephalitis. Ann Neurol 2002;51:311‐18. 7. Press C, Wallace A, Chapman KE. The Janus of Rasmussens’ Encephalitis. Sem Pediatr Neurol 2014:xxxxx 8. Oguni H, Anderman F, Rasmussen TB. The natural history of the syndrome of chronic encephalitis and epilepsy: a study of the MNI series of forty eight cases. In Anderman F (ed) Chronic Encephalitis and Epilepsy: Rasmussen’s Syndrome. Boston MA, Butterworth‐ Heinemann, p 7‐35. 9. Gambardella A, Andermann F, Shorvon S, et al. Limited chronic focal encephalitis: another variant of Rasmussen syndrome. Neurology 2008;70:374‐7. 10. Frucht S. Dystonia, athetosis and epilepsia partialis continua in a patient with late‐onset Rasmussen’s encephalitis. Mov Disord 2002;17:609‐12. 11. Bien CG, Elger CE, Leitner Y et al. Slowly progressive hemiparesis in childhood as a consequence of Rasmussen encephalitis without or with delayed‐onset seizures. Eur J Neurol 2007;14:387‐90. 12. Andermann F, Farrell K. Early onset Rasmussen’s syndrome: a malignant often bilateral form of the disorder. Epilepsy Res 2006;70 (suppl): S259‐62. 13. Hart YM, Andermann F, Robitaille Y, et al. Double pathology in Rasmussen’s syndrome: a window on the etiology. Neurology 1998;50:731‐5. 14. Takai H, Wilfong A, Malphrus A, et al. Dual pathology in Rasmussen’s encephalitis: a study of seven cases and review of the literature. Neuropathology 2010;30:381‐91.
