Download PDF
Semin Neurol 2015; 35(03): 259-268
DOI: 10.1055/s-0035-1552921
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Rasmussen Syndrome and Other Inflammatory Epilepsies

Sophia Varadkar
1   Epilepsy Unit, Great Ormond Street Hospital for Children NHS Foundation Trust and UCL Institute of Child Health, London, United Kingdom
,
J. Helen Cross
2   Department of Clinical Neurosciences, UCL-Institute of Child Health, Great Ormond Street for Children NHS Foundation Trust, London and Young Epilepsy, Lingfield, United Kingdom
› Author Affiliations
Further Information

Publication History

Publication Date:
10 June 2015 (online)

   Permissions and Reprints

Abstract

An underlying immune basis is emerging in an increasing number of epileptic and encephalopathic syndromes. The immunopathological mechanisms may be categorized into antibody-mediated, T-cell cytotoxicity, and microglia-induced degeneration. The immune basis in Rasmussen syndrome is thought to be T-cell mediated. Antibodies to extracellular and intracellular epitopes are implicated in limbic and other encephalitides, characterized by seizures, movement disorder, sleep disorder, obtundation, psychosis, mutism, and other psychiatric symptoms. Extracellular antibodies are directed at cell-surface-expressed neuronal or glial proteins: glutamate receptors (N-methyl-D-aspartate and α-amino-3-hydroxy-5-methyl-4-isoxazol-propionic acid), voltage-gated potassium channel complex (contactin-associated-protein 2 [CASPR2], contactin-2 and leucin-rich, glioma-inactivated 1 [LGI1]), and γ-aminobutyric acid (GABA) receptors (GABABR and GABAAR). Antibodies to intracellular antigens are less commonly seen (for example, glutamic acid decarboxylase). Diseases caused by antibodies to cell-surface-expressed antigens are better expected to respond to immune treatments than to those where the presumed mechanism is T-cell driven. Antibodies to the folate receptor FR1 are a cause of primary cerebral folate deficiency. Febrile infection-related epilepsy syndrome (FIRES) may also have an immune basis, although this is yet to be proven. For all these epilepsies, the best treatment and the long-term outcomes are not yet clear.

Keywords

Rasmussen syndrome - Rasmussen encephalitis - epilepsy - immune - antibody - encephalitis - N-methyl-D-aspartate receptor - voltage-gated potassium channel - febrile infection-related epilepsy syndrome
 

  • References

  • 1 Varadkar S, Bien CG, Kruse CA , et al. Rasmussen's encephalitis: clinical features, pathobiology, and treatment advances. Lancet Neurol 2014; 13 (2) 195-205
    CrossrefPubMedGoogle Scholar
  • 2 Rogers SW, Andrews PI, Gahring LC , et al. Autoantibodies to glutamate receptor GluR3 in Rasmussen's encephalitis. Science 1994; 265 (5172) 648-651
    CrossrefPubMedGoogle Scholar
  • 3 Irani SR, Gelfand JM, Al-Diwani A, Vincent A. Cell-surface central nervous system autoantibodies: clinical relevance and emerging paradigms. Ann Neurol 2014; 76 (2) 168-184
    CrossrefPubMedGoogle Scholar
  • 4 Vincent A, Bien CG, Irani SR, Waters P. Autoantibodies associated with diseases of the CNS: new developments and future challenges. Lancet Neurol 2011; 10 (8) 759-772
    CrossrefPubMedGoogle Scholar
  • 5 Dalmau J, Lancaster E, Martinez-Hernandez E, Rosenfeld MR, Balice-Gordon R. Clinical experience and laboratory investigations in patients with anti-NMDAR encephalitis. Lancet Neurol 2011; 10 (1) 63-74
    Google Scholar
  • 6 Buckley C, Oger J, Clover L , et al. Potassium channel antibodies in two patients with reversible limbic encephalitis. Ann Neurol 2001; 50 (1) 73-78
    CrossrefPubMedGoogle Scholar
  • 7 Lai M, Hughes EG, Peng X , et al. AMPA receptor antibodies in limbic encephalitis alter synaptic receptor location. Ann Neurol 2009; 65 (4) 424-434
    CrossrefPubMedGoogle Scholar
  • 8 Lancaster E, Lai M, Peng X , et al. Antibodies to the GABA(B) receptor in limbic encephalitis with seizures: case series and characterisation of the antigen. Lancet Neurol 2010; 9 (1) 67-76
    CrossrefPubMedGoogle Scholar
  • 9 Petit-Pedrol M, Armangue T, Peng X , et al. Encephalitis with refractory seizures, status epilepticus, and antibodies to the GABAA receptor: a case series, characterisation of the antigen, and analysis of the effects of antibodies. Lancet Neurol 2014; 13 (3) 276-286
    CrossrefPubMedGoogle Scholar
  • 10 Pettingill P, Kramer HB, Coebergh JA , et al. Antibodies to GABAA receptor α1 and γ2 subunits: Clinical and serologic characterization. Neurology 2015; 84 (12) 1233-1241
    CrossrefPubMedGoogle Scholar
  • 11 Malter MP, Helmstaedter C, Urbach H, Vincent A, Bien CG. Antibodies to glutamic acid decarboxylase define a form of limbic encephalitis. Ann Neurol 2010; 67 (4) 470-478
    CrossrefPubMedGoogle Scholar
  • 12 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
    CrossrefPubMedGoogle Scholar
  • 13 Bien CG, Tiemeier H, Sassen R , et al. Rasmussen encephalitis: incidence and course under randomized therapy with tacrolimus or intravenous immunoglobulins. Epilepsia 2013; 54 (3) 543-550
    CrossrefPubMedGoogle Scholar
  • 14 Lamb K, Scott WJ, Mensah A, Robinson R, Varadkar S, Cross JH. Prevalence and clinical outcome of Rasmussen encephalitis in children from the United Kingdom. Dev Med Child Neurol 2013; 55 (Suppl. 01) 14
    PubMedGoogle Scholar
  • 15 Oguni H, Andermann 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: Andermann F, , ed. Chronic Encephalitis and Epilepsy–Rasmussen's Syndrome. Boston, MA: Butterworth-Heinemann; 1991: 7-35
    Google Scholar
  • 16 Frucht S. Dystonia, athetosis, and epilepsia partialis continua in a patient with late-onset Rasmussen's encephalitis. Mov Disord 2002; 17 (3) 609-612
    CrossrefPubMedGoogle Scholar
  • 17 Bien CGM, Urbach H, Deckert M , et al. Diagnosis and staging of Rasmussen's encephalitis by serial MRI and histopathology. Neurology 2002; 58 (2) 250-257
    CrossrefPubMedGoogle Scholar
  • 18 Longaretti F, Dunkley C, Varadkar S, Vargha-Khadem F, Boyd SG, Cross JH. Evolution of the EEG in children with Rasmussen's syndrome. Epilepsia 2012; 53 (9) 1539-1545
    CrossrefPubMedGoogle Scholar
  • 19 Pardo CA, Vining EPG, Guo L, Skolasky RL, Carson BS, Freeman JM. The pathology of Rasmussen syndrome: stages of cortical involvement and neuropathological studies in 45 hemispherectomies. Epilepsia 2004; 45 (5) 516-526
    CrossrefPubMedGoogle Scholar
  • 20 Watson R, Jepson JE, Bermudez I , et al. Alpha7-acetylcholine receptor antibodies in two patients with Rasmussen encephalitis. Neurology 2005; 65 (11) 1802-1804
    CrossrefPubMedGoogle Scholar
  • 21 Watson R, Jiang Y, Bermudez I , et al. Absence of antibodies to glutamate receptor type 3 (GluR3) in Rasmussen encephalitis. Neurology 2004; 63 (1) 43-50
    CrossrefPubMedGoogle Scholar
  • 22 Yang R, Puranam RS, Butler LS , et al. Autoimmunity to munc-18 in Rasmussen's encephalitis. Neuron 2000; 28 (2) 375-383
    CrossrefPubMedGoogle Scholar
  • 23 Spitz MA, Dubois-Teklali F, Vercueil L , et al. Voltage-gated potassium channels autoantibodies in a child with rasmussen encephalitis. Neuropediatrics 2014; 45 (5) 336-340
    Article in Thieme ConnectPubMedGoogle Scholar
  • 24 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
    CrossrefPubMedGoogle Scholar
  • 25 Aronica E, Ravizza T, Zurolo E, Vezzani A. Astrocyte immune responses in epilepsy. Glia 2012; 60 (8) 1258-1268
    CrossrefPubMedGoogle Scholar
  • 26 Bauer J, Elger CE, Hans VH , et al. Astrocytes are a specific immunological target in Rasmussen's encephalitis. Ann Neurol 2007; 62 (1) 67-80
    CrossrefPubMedGoogle Scholar
  • 27 Owens GC, Huynh MN, Chang JW , et al. Differential expression of interferon-γ and chemokine genes distinguishes Rasmussen encephalitis from cortical dysplasia and provides evidence for an early Th1 immune response. J Neuroinflammation 2013; 10: 56
    CrossrefPubMedGoogle Scholar
  • 28 Dalmau J, Tüzün E, Wu HY , et al. Paraneoplastic anti-N-methyl-D-aspartate receptor encephalitis associated with ovarian teratoma. Ann Neurol 2007; 61 (1) 25-36
    Google Scholar
  • 29 Florance NR, Davis RL, Lam C , et al. Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis in children and adolescents. Ann Neurol 2009; 66 (1) 11-18
    CrossrefPubMedGoogle Scholar
  • 30 Armangue T, Titulaer MJ, Málaga I , et al; Spanish Anti-N-methyl-D-Aspartate Receptor (NMDAR) Encephalitis Work Group. Pediatric anti-N-methyl-D-aspartate receptor encephalitis-clinical analysis and novel findings in a series of 20 patients. J Pediatr 2013; 162 (4) 850-856.e2
    CrossrefPubMedGoogle Scholar
  • 31 Wright S, Hacohen Y, Jacobson L , et al. N-methyl-D-aspartate receptor antibody-mediated neurological disease: results of a UK-based surveillance study in children. Arch Dis Child 2015;
    PubMedGoogle Scholar
  • 32 Dalmau J, Gleichman AJ, Hughes EG , et al. Anti-NMDA-receptor encephalitis: case series and analysis of the effects of antibodies. Lancet Neurol 2008; 7 (12) 1091-1098
    CrossrefPubMedGoogle Scholar
  • 33 Hacohen Y, Wright S, Waters P , et al. Paediatric autoimmune encephalopathies: clinical features, laboratory investigations and outcomes in patients with or without antibodies to known central nervous system autoantigens. J Neurol Neurosurg Psychiatry 2013; 84 (7) 748-755
    CrossrefPubMedGoogle Scholar
  • 34 Greiner H, Leach JL, Lee KH, Krueger DA. Anti-NMDA receptor encephalitis presenting with imaging findings and clinical features mimicking Rasmussen syndrome. Seizure 2011; 20 (3) 266-270
    CrossrefPubMedGoogle Scholar
  • 35 Gresa-Arribas N, Titulaer MJ, Torrents A , et al. Antibody titres at diagnosis and during follow-up of anti-NMDA receptor encephalitis: a retrospective study. Lancet Neurol 2014; 13 (2) 167-177
    CrossrefPubMedGoogle Scholar
  • 36 Titulaer MJ, McCracken L, Gabilondo I , et al. Treatment and prognostic factors for long-term outcome in patients with anti-NMDA receptor encephalitis: an observational cohort study. Lancet Neurol 2013; 12 (2) 157-165
    CrossrefPubMedGoogle Scholar
  • 37 Irani SR, Alexander S, Waters P , et al. Antibodies to Kv1 potassium channel-complex proteins leucine-rich, glioma inactivated 1 protein and contactin-associated protein-2 in limbic encephalitis, Morvan's syndrome and acquired neuromyotonia. Brain 2010; 133 (9) 2734-2748
    CrossrefPubMedGoogle Scholar
  • 38 Haberlandt E, Bast T, Ebner A , et al. Limbic encephalitis in children and adolescents. Arch Dis Child 2011; 96 (2) 186-191
    CrossrefPubMedGoogle Scholar
  • 39 Morante-Redolat JM, Gorostidi-Pagola A, Piquer-Sirerol S , et al. Mutations in the LGI1/Epitempin gene on 10q24 cause autosomal dominant lateral temporal epilepsy. Hum Mol Genet 2002; 11 (9) 1119-1128
    CrossrefPubMedGoogle Scholar
  • 40 Strauss KA, Puffenberger EG, Huentelman MJ , et al. Recessive symptomatic focal epilepsy and mutant contactin-associated protein-like 2. N Engl J Med 2006; 354 (13) 1370-1377
    CrossrefPubMedGoogle Scholar
  • 41 Höftberger R, Titulaer MJ, Sabater L , et al. Encephalitis and GABAB receptor antibodies: novel findings in a new case series of 20 patients. Neurology 2013; 81 (17) 1500-1506
    CrossrefPubMedGoogle Scholar
  • 42 Kwan P, Sills GJ, Kelly K, Butler E, Brodie MJ. Glutamic acid decarboxylase autoantibodies in controlled and uncontrolled epilepsy: a pilot study. Epilepsy Res 2000; 42 (2-3) 191-195
    CrossrefPubMedGoogle Scholar
  • 43 Brenner T, Sills GJ, Hart Y , et al. Prevalence of neurologic autoantibodies in cohorts of patients with new and established epilepsy. Epilepsia 2013; 54 (6) 1028-1035
    CrossrefPubMedGoogle Scholar
  • 44 Dahm L, Ott C, Steiner J , et al. Seroprevalence of autoantibodies against brain antigens in health and disease. Ann Neurol 2014; 76 (1) 82-94
    CrossrefPubMedGoogle Scholar
  • 45 Levin EC, Acharya NK, Han M , et al. Brain-reactive autoantibodies are nearly ubiquitous in human sera and may be linked to pathology in the context of blood-brain barrier breakdown. Brain Res 2010; 1345 (0) 221-232
    CrossrefPubMedGoogle Scholar
  • 46 Hyland K, Shoffner J, Heales SJ. Cerebral folate deficiency. J Inherit Metab Dis 2010; 33 (5) 563-570
    CrossrefPubMedGoogle Scholar
  • 47 Ramaekers VT, Rothenberg SP, Sequeira JM , et al. Autoantibodies to folate receptors in the cerebral folate deficiency syndrome. N Engl J Med 2005; 352 (19) 1985-1991
    CrossrefPubMedGoogle Scholar
  • 48 Ramaekers VT, Sequeira JM, Blau N, Quadros EV. A milk-free diet downregulates folate receptor autoimmunity in cerebral folate deficiency syndrome. Dev Med Child Neurol 2008; 50 (5) 346-352
    CrossrefPubMedGoogle Scholar
  • 49 Kramer U, Chi CS, Lin KL , et al. Febrile infection-related epilepsy syndrome (FIRES): pathogenesis, treatment, and outcome: a multicenter study on 77 children. Epilepsia 2011; 52 (11) 1956-1965
    CrossrefPubMedGoogle Scholar
  • 50 Milh M, Villeneuve N, Chapon F , et al. New onset refractory convulsive status epilepticus associated with serum neuropil auto-antibodies in a school aged child. Brain Dev 2011; 33 (8) 687-691
    CrossrefPubMedGoogle Scholar
  • 51 Illingworth MA, Hanrahan D, Anderson CE , et al. Elevated VGKC-complex antibodies in a boy with fever-induced refractory epileptic encephalopathy in school-age children (FIRES). Dev Med Child Neurol 2011; 53 (11) 1053-1057
    CrossrefPubMedGoogle Scholar
  • 52 van Baalen A, Hausler M, Plecko-Startinig B , et al. Febrile Infection Related Epilepsy Syndrome without detectable antibodies and response to immunotherapy: a case series and discussion of epileptogenesis in FIRES. Neuropediatrics 2012; 43: 209-216
    Article in Thieme ConnectPubMedGoogle Scholar
  • 53 Carranza Rojo D, Harvey AS, Iona X , et al. Febrile infection-related epilepsy syndrome is not caused by SCN1A mutations. Epilepsy Res 2012; 100 (1-2) 194-198
    CrossrefPubMedGoogle Scholar
  • 54 Appenzeller S, Helbig I, Stephani U , et al. Febrile infection-related epilepsy syndrome (FIRES) is not caused by SCN1A, POLG, PCDH19 mutations or rare copy number variations. Dev Med Child Neurol 2012; 54 (12) 1144-1148
    CrossrefPubMedGoogle Scholar
  • 55 Specchio N, Fusco L, Claps D, Vigevano F. Epileptic encephalopathy in children possibly related to immune-mediated pathogenesis. Brain Dev 2010; 32 (1) 51-56
    CrossrefPubMedGoogle Scholar
  • 56 Nabbout R, Mazzuca M, Hubert P , et al. Efficacy of ketogenic diet in severe refractory status epilepticus initiating fever induced refractory epileptic encephalopathy in school age children (FIRES). Epilepsia 2010; 51 (10) 2033-2037
    CrossrefPubMedGoogle Scholar
  • 57 Nabbout R, Vezzani A, Dulac O, Chiron C. Acute encephalopathy with inflammation-mediated status epilepticus. Lancet Neurol 2011; 10 (1) 99-108
    CrossrefPubMedGoogle Scholar
  • 58 Bittner S, Simon OJ, Göbel K, Bien CG, Meuth SG, Wiendl H. Rasmussen encephalitis treated with natalizumab. Neurology 2013; 81 (4) 395-397
    CrossrefPubMedGoogle Scholar
  • 59 Thilo B, Stingele R, Knudsen K , et al. A case of Rasmussen encephalitis treated with rituximab. Nat Rev Neurol 2009; 5 (8) 458-462
    CrossrefPubMedGoogle Scholar