Research advancement on immunopathology and characteristic double pathology of Rasmussen encephalitis_Journal of Epilepsy

Authors：

QIAO Jiao , GONG Mingkun , TANG Chongyang ,  LUAN Guoming

Epilepsy Center, Sanbo Brain Hospital, Capital Medical University, Beijing 100093, China;

Corresponding author：

LUAN Guoming, Email: luangm@ccmu.edu.cn

Keywords：

Immunopathology; Rasmussen’s encephalitis; Epilepsy

DOI：

10.7507/2096-0247.202312002

Video：

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Rasmussen’s encephalitis (RE) is a rare neurologic disorder, with an incidence of 0.18 per 100,000 population, primarily affecting children, with an average onset at 6-7 years of age. Clinical manifestations include focal refractory epilepsy, progressive neurological deterioration, and cognitive decline. In imaging, magnetic resonance imaging (MRI) typically shows an increase in volume and sequences with T2/fluid-attenuated inversion recovery (FLAIR) signal, followed by atrophy. Positron emission tomography (PET) demonstrates a decline in metabolism in one hemisphere. Pathologically, neuronal loss, perivascular lymphocytic cuffing, and small glial nodules are prominent, with 10% of cases exhibiting dual pathology, primarily cortical dysplasia. Functional hemispherectomy remains the only therapeutic option, albeit resulting in permanent motor and cognitive deficits. Immunomodulatory therapy provides only temporary relief. Currently, the etiology and pathogenesis of RE remain unclear, presenting three major challenges: early diagnosis before hemisphere atrophy and neurocognitive impairment, managing immune therapies targeting inflammation, and determining rehabilitation post-surgery to maximize neurological recovery. Emerging evidence suggests that alterations in the brain’s immune microenvironment play a pivotal role in disease progression. This article focuses on the immunopathological aspects of RE, elucidating the roles of T lymphocytes, small glial cells, and astrocytes in the development of RE.

Citation： QIAO Jiao, GONG Mingkun, TANG Chongyang, LUAN Guoming. Research advancement on immunopathology and characteristic double pathology of Rasmussen encephalitis. Journal of Epilepsy, 2024, 10(1): 78-82. doi: 10.7507/2096-0247.202312002 Copy

1.	Varadkar S, Bien CG, Kruse CA, et al. Rasmussen's encephalitis: clinical features, pathobiology, and treatment advances. The Lancet Neurology, 2014, 13(2): 195-205.
2.	Bien CG, Granata T, Antozzi C, et al. Pathogenesis, diagnosis and treatment of Rasmussen encephalitis: a European consensus statement. Brain, 2005, 128(Pt 3): 454-471.
3.	Jay V, Becker LE, Otsubo H, et al. Chronic encephalitis and epilepsy (Rasmussen's encephalitis): detection of cytomegalovirus and herpes simplex virus 1 by the polymerase chain reaction and in situ hybridization. Neurology, 1995, 45(1): 108-117.
4.	Power C, Poland SD, Blume WT, et al. Cytomegalovirus and Rasmussen's encephalitis. Lancet, 1990, 336(8726): 1282-1284.
5.	Wiendl H, Bien CG, Bernasconi P, et al. GluR3 antibodies: prevalence in focal epilepsy but no specificity for Rasmussen's encephalitis. Neurology, 2001, 57(8): 1511-1514.
6.	Atkins MR, Terrell W, Hulette CM. Rasmussen's syndrome: a study of potential viral etiology. Clin Neuropathol, 1995, 14(1): 7-12.
7.	Pardo CA, Vining EP, Guo L, et al. The pathology of Rasmussen syndrome: stages of cortical involvement and neuropathological studies in 45 hemispherectomies. Epilepsia, 2004, 45(5): 516-26.
8.	Tang C, Yang W, Luan G. Progress in pathogenesis and therapy of Rasmussen's encephalitis. Acta Neurol Scand, 2022, 146(6): 761-766.
9.	Bien CG, Urbach H, Deckert M, et al. Diagnosis and staging of Rasmussen's encephalitis by serial MRI and histopathology. Neurology, 2002, 58(2): 250-257.
10.	Schwab N, Bien CG, Waschbisch A, et al. CD8+ T-cell clones dominate brain infiltrates in Rasmussen encephalitis and persist in the periphery. Brain, 2009, 132(Pt 5): 1236-1246.
11.	Bauer J, Eiger CE, Hans VH, et al. Astrocytes are a specific immunological target in Rasmussen's encephalitis. Annals of Neurology, 2007, 62(1): 67-80.
12.	Schneider-Hohendorf T, Mohan H, Bien CG, et al. CD8(+) T-cell pathogenicity in Rasmussen encephalitis elucidated by large-scale T-cell receptor sequencing. Nature Communications, 2016, 7: 145-152.
13.	Troscher AR, Wimmer I, Quemada-Garrido L, et al. Microglial nodules provide the environment for pathogenic T cells in human encephalitis. Acta Neuropathologica, 2019, 137(4): 619-635.
14.	Kebir H, Carmant L, Fontaine F, et al. Humanized mouse model of Rasmussen's encephalitis supports the immune-mediated hypothesis. Journal of Clinical Investigation, 2018, 128(5): 2000-2009.
15.	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(3): 311-318.
16.	Di Liberto G, Pantelyushin S, Kreutzfeldt M, et al. Neurons under T Cell Attack Coordinate Phagocyte-Mediated Synaptic Stripping. Cell, 2018, 175(2): 458-471.
17.	Takahashi Y, Mine J, Kubota Y, et al. A substantial number of Rasmussen syndrome patients have increased IgG, CD4+ T cells, TNFalpha, and Granzyme B in CSF. Epilepsia, 2009, 50(6): 1419-1431.
18.	Owens GC, Huynh MN, Chang JW, et al. Differential expression of interferon-gamma and chemokine genes distinguishes Rasmussen encephalitis from cortical dysplasia and provides evidence for an early Th1 immune response. J Neuroinflammation, 2013, 10: 56.
19.	Owens GC, Erickson KL, Malone CC, et al. Evidence for the involvement of gamma delta T cells in the immune response in Rasmussen encephalitis. J Neuroinflammation, 2015, 12: 134.
20.	Dong C. Cytokine Regulation and Function in T Cells. Annu Rev Immunol, 2021, 39: 51-76.
21.	Wirenfeldt M, Clare R, Tung S, et al. Increased activation of Iba1+ microglia in pediatric epilepsy patients with Rasmussen's encephalitis compared with cortical dysplasia and tuberous sclerosis complex. Neurobiol Dis, 2009, 34(3): 432-440.
22.	Banati RB, Goerres GW, Myers R, et al. [11C](R)-PK11195 positron emission tomography imaging of activated microglia in vivo in Rasmussen’s encephalitis. Neurology, 1999, 53(9): 2199-2199.
23.	Eyo UB, Murugan M, Wu LJ. Microglia-Neuron Communication in Epilepsy. Glia, 2017, 65(1): 5-18.
24.	Ramaswamy V, Walsh JG, Sinclair DB, et al. Inflammasome induction in Rasmussen's encephalitis: cortical and associated white matter pathogenesis. J Neuroinflammation, 2013, 10: 152.
25.	Tang C, Wang X, Deng J, et al. Increased inflammasome-activated pyroptosis mediated by caspase-1 in Rasmussen's encephalitis. Epilepsy Res, 2021, 179: 106843.
26.	Cepeda C, Chang JW, Owens G C, et al. In Rasmussen encephalitis, hemichannels associated with microglial activation are linked to cortical pyramidal neuron coupling: a possible mechanism for cellular hyperexcitability. CNS Neurosci Ther, 2015, 21(2): 152-163.
27.	Westfall JJ, Schwind WN, Sran S, et al. Molecular and spatial heterogeneity of microglia in Rasmussen encephalitis. Acta Neuropathol Commun, 2022, 10(1): 168.
28.	Leitner DF, Lin Z, Sawaged Z, et al. Brain molecular mechanisms in Rasmussen encephalitis. Epilepsia, 2023, 64(1): 218-230.
29.	Manning T, Sontheimer HJG. Spontaneous intracellular calcium oscillations in cortical astrocytes from a patient with intractable childhood epilepsy (Rasmussen's encephalitis). Glia, 1997, 21(3): 332-337.
30.	Sofroniew MV, Vinters HV. Astrocytes: biology and pathology. Acta Neuropathol, 2010, 119(1): 7-35.
31.	Luan G, Gao Q, Guan Y, et al. Upregulation of adenosine kinase in Rasmussen encephalitis. J Neuropathol Exp Neurol, 2013, 72(11): 1000-1008.
32.	Luan G, Wang X, Gao Q, et al. Upregulation of Neuronal Adenosine A1 Receptor in Human Rasmussen Encephalitis. J Neuropathol Exp Neurol, 2017, 76(8): 720-731.
33.	He X, Chen F, Zhang Y, et al. Upregulation of adenosine A2A receptor and downregulation of GLT1 is associated with neuronal cell death in Rasmussen's encephalitis. Brain Pathol, 2020, 30(2): 246-260.
34.	Rasmussen T, Olszewski J, Lloydsmith D. Focal seizures due to chronic localized encephalitis. Neurology, 1958, 8(6): 435-445.
35.	Bien CG, Widman G, Urbach H, et al. The natural history of Rasmussen's encephalitis. Brain, 2002, 125(Pt 8): 1751-1759.
36.	Kruse CA, Pardo CA, Hartman AL, et al. Rasmussen encephalitis tissue transfer program. Epilepsia, 2016, 57(6): 1005-1007.

1. Varadkar S, Bien CG, Kruse CA, et al. Rasmussen's encephalitis: clinical features, pathobiology, and treatment advances. The Lancet Neurology, 2014, 13(2): 195-205.
2. Bien CG, Granata T, Antozzi C, et al. Pathogenesis, diagnosis and treatment of Rasmussen encephalitis: a European consensus statement. Brain, 2005, 128(Pt 3): 454-471.
3. Jay V, Becker LE, Otsubo H, et al. Chronic encephalitis and epilepsy (Rasmussen's encephalitis): detection of cytomegalovirus and herpes simplex virus 1 by the polymerase chain reaction and in situ hybridization. Neurology, 1995, 45(1): 108-117.
4. Power C, Poland SD, Blume WT, et al. Cytomegalovirus and Rasmussen's encephalitis. Lancet, 1990, 336(8726): 1282-1284.
5. Wiendl H, Bien CG, Bernasconi P, et al. GluR3 antibodies: prevalence in focal epilepsy but no specificity for Rasmussen's encephalitis. Neurology, 2001, 57(8): 1511-1514.
6. Atkins MR, Terrell W, Hulette CM. Rasmussen's syndrome: a study of potential viral etiology. Clin Neuropathol, 1995, 14(1): 7-12.
7. Pardo CA, Vining EP, Guo L, et al. The pathology of Rasmussen syndrome: stages of cortical involvement and neuropathological studies in 45 hemispherectomies. Epilepsia, 2004, 45(5): 516-26.
8. Tang C, Yang W, Luan G. Progress in pathogenesis and therapy of Rasmussen's encephalitis. Acta Neurol Scand, 2022, 146(6): 761-766.
9. Bien CG, Urbach H, Deckert M, et al. Diagnosis and staging of Rasmussen's encephalitis by serial MRI and histopathology. Neurology, 2002, 58(2): 250-257.
10. Schwab N, Bien CG, Waschbisch A, et al. CD8+ T-cell clones dominate brain infiltrates in Rasmussen encephalitis and persist in the periphery. Brain, 2009, 132(Pt 5): 1236-1246.
11. Bauer J, Eiger CE, Hans VH, et al. Astrocytes are a specific immunological target in Rasmussen's encephalitis. Annals of Neurology, 2007, 62(1): 67-80.
12. Schneider-Hohendorf T, Mohan H, Bien CG, et al. CD8(+) T-cell pathogenicity in Rasmussen encephalitis elucidated by large-scale T-cell receptor sequencing. Nature Communications, 2016, 7: 145-152.
13. Troscher AR, Wimmer I, Quemada-Garrido L, et al. Microglial nodules provide the environment for pathogenic T cells in human encephalitis. Acta Neuropathologica, 2019, 137(4): 619-635.
14. Kebir H, Carmant L, Fontaine F, et al. Humanized mouse model of Rasmussen's encephalitis supports the immune-mediated hypothesis. Journal of Clinical Investigation, 2018, 128(5): 2000-2009.
15. 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(3): 311-318.
16. Di Liberto G, Pantelyushin S, Kreutzfeldt M, et al. Neurons under T Cell Attack Coordinate Phagocyte-Mediated Synaptic Stripping. Cell, 2018, 175(2): 458-471.
17. Takahashi Y, Mine J, Kubota Y, et al. A substantial number of Rasmussen syndrome patients have increased IgG, CD4+ T cells, TNFalpha, and Granzyme B in CSF. Epilepsia, 2009, 50(6): 1419-1431.
18. Owens GC, Huynh MN, Chang JW, et al. Differential expression of interferon-gamma and chemokine genes distinguishes Rasmussen encephalitis from cortical dysplasia and provides evidence for an early Th1 immune response. J Neuroinflammation, 2013, 10: 56.
19. Owens GC, Erickson KL, Malone CC, et al. Evidence for the involvement of gamma delta T cells in the immune response in Rasmussen encephalitis. J Neuroinflammation, 2015, 12: 134.
20. Dong C. Cytokine Regulation and Function in T Cells. Annu Rev Immunol, 2021, 39: 51-76.
21. Wirenfeldt M, Clare R, Tung S, et al. Increased activation of Iba1+ microglia in pediatric epilepsy patients with Rasmussen's encephalitis compared with cortical dysplasia and tuberous sclerosis complex. Neurobiol Dis, 2009, 34(3): 432-440.
22. Banati RB, Goerres GW, Myers R, et al. [11C](R)-PK11195 positron emission tomography imaging of activated microglia in vivo in Rasmussen’s encephalitis. Neurology, 1999, 53(9): 2199-2199.
23. Eyo UB, Murugan M, Wu LJ. Microglia-Neuron Communication in Epilepsy. Glia, 2017, 65(1): 5-18.
24. Ramaswamy V, Walsh JG, Sinclair DB, et al. Inflammasome induction in Rasmussen's encephalitis: cortical and associated white matter pathogenesis. J Neuroinflammation, 2013, 10: 152.
25. Tang C, Wang X, Deng J, et al. Increased inflammasome-activated pyroptosis mediated by caspase-1 in Rasmussen's encephalitis. Epilepsy Res, 2021, 179: 106843.
26. Cepeda C, Chang JW, Owens G C, et al. In Rasmussen encephalitis, hemichannels associated with microglial activation are linked to cortical pyramidal neuron coupling: a possible mechanism for cellular hyperexcitability. CNS Neurosci Ther, 2015, 21(2): 152-163.
27. Westfall JJ, Schwind WN, Sran S, et al. Molecular and spatial heterogeneity of microglia in Rasmussen encephalitis. Acta Neuropathol Commun, 2022, 10(1): 168.
28. Leitner DF, Lin Z, Sawaged Z, et al. Brain molecular mechanisms in Rasmussen encephalitis. Epilepsia, 2023, 64(1): 218-230.
29. Manning T, Sontheimer HJG. Spontaneous intracellular calcium oscillations in cortical astrocytes from a patient with intractable childhood epilepsy (Rasmussen's encephalitis). Glia, 1997, 21(3): 332-337.
30. Sofroniew MV, Vinters HV. Astrocytes: biology and pathology. Acta Neuropathol, 2010, 119(1): 7-35.
31. Luan G, Gao Q, Guan Y, et al. Upregulation of adenosine kinase in Rasmussen encephalitis. J Neuropathol Exp Neurol, 2013, 72(11): 1000-1008.
32. Luan G, Wang X, Gao Q, et al. Upregulation of Neuronal Adenosine A1 Receptor in Human Rasmussen Encephalitis. J Neuropathol Exp Neurol, 2017, 76(8): 720-731.
33. He X, Chen F, Zhang Y, et al. Upregulation of adenosine A2A receptor and downregulation of GLT1 is associated with neuronal cell death in Rasmussen's encephalitis. Brain Pathol, 2020, 30(2): 246-260.
34. Rasmussen T, Olszewski J, Lloydsmith D. Focal seizures due to chronic localized encephalitis. Neurology, 1958, 8(6): 435-445.
35. Bien CG, Widman G, Urbach H, et al. The natural history of Rasmussen's encephalitis. Brain, 2002, 125(Pt 8): 1751-1759.
36. Kruse CA, Pardo CA, Hartman AL, et al. Rasmussen encephalitis tissue transfer program. Epilepsia, 2016, 57(6): 1005-1007.

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Research advancement on immunopathology and characteristic double pathology of Rasmussen encephalitis

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