Febrile Infection-Related Epilepsy Syndrome without Detectable Autoantibodies and Response to Immunotherapy: A Case Series and Discussion of Epileptogenesis in FIRES

Abstract

Febrile infection-related epilepsy syndrome (FIRES) is a severe postinfectious epileptic encephalopathy in previously healthy children and has three phases: the initial phase with a simple febrile infection, a few days later the acute phase characterized by a peracute onset of highly recurrent seizures or refractory status epilepticus often with no more fever and generally without additional neurological features (the classical pure seizure phenotype), and last, the chronic phase with a drug-resistant epilepsy and neuropsychological impairments. FIRES seems to be sporadic and very rare: we estimated the annual incidence in children and adolescents by a prospective hospital-based German-wide surveillance as 1 in 1,000,000. Because of the preceding infection and lacking evidence of infectious encephalitis, an immune-mediated pathomechanism and, therefore, a response to immunotherapies may be involved. To test the hypothesis that antibodies against neuronal structures cause FIRES, we analyzed sera of 12 patients aged 2 to 12 years (median 6 years) and cerebral spinal fluids (CSFs) of 3 of these 12 patients with acute or chronic FIRES. We studied six patients (two including CSF) 1 to 14 weeks (median 3 weeks) and six patients 1 to 6 years (median 3.5 years) after seizure onset. All samples were analyzed for antibodies against glutamate receptors of type N-methyl-D-aspartate (NMDA) and type α-amino-3-hydroxy-5-methyl-4-isoxazoleproprionic acid (AMPA), gamma-aminobutyric acid (GABA)_B-receptors, voltage-gated potassium channel (VGKC)-associated proteins leucin-rich glioma inactivated 1 (LGI1) and contactin-associated protein like 2 (CASPR2), and glutamic acid decarboxylase (GAD) by a multiparametric recombinant immunofluorescence assay employing human embryonic kidney (HEK) cells transfected with cDNAs for the antigens. In addition, indirect immunohistochemistry using rat whole-brain sections was done in three patients. Finally, sera of 10 patients were tested for VGKC complex antibodies by radioimmunoprecipitation assay (RIA). None of the antibody tests were positive in any of the patients. Moreover, steroids, immunoglobulins, and plasmapheresis had no clear effect in the seven patients receiving immunotherapy. The failure of antibody-detection against the known neuronal antigens as well as the ineffectiveness of immunotherapy questions a role for autoantibodies in the epileptogenesis of classical FIRES. As we discuss, other underlying causes need to be considered including the possibility of a mitochondrial encephalopathy.

Keywords

antibody - epilepsy - fires - immunotherapy - infection - inflammation - status epilepticus

• References

• 1 Sakuma H, Awaya Y, Shiomi M , et al. Acute encephalitis with refractory, repetitive partial seizures (AERRPS): a peculiar form of childhood encephalitis. Acta Neurol Scand 2010; 121 (4) 251-256
• 2 Mikaeloff Y, Jambaqué I, Hertz-Pannier L , et al. Devastating epileptic encephalopathy in school-aged children (DESC): a pseudo encephalitis. Epilepsy Res 2006; 69 (1) 67-79
• 3 Wilder-Smith EP, Lim EC, Teoh HL , et al. The NORSE (new-onset refractory status epilepticus) syndrome: defining a disease entity. Ann Acad Med Singapore 2005; 34 (7) 417-420
• 4 van Baalen A, Häusler M, Boor R , et al. Febrile infection-related epilepsy syndrome (FIRES): a nonencephalitic encephalopathy in childhood. Epilepsia 2010; 51 (7) 1323-1328
• 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
• 6 Irani SR, Vincent A, Schott JM. Autoimmune encephalitis. BMJ 2011; 342: d1918
• 7 Vezzani A, French J, Bartfai T, Baram TZ. The role of inflammation in epilepsy. Nat Rev Neurol 2011; 7 (1) 31-40
• 8 Nabbout R, Vezzani A, Dulac O, Chiron C. Acute encephalopathy with inflammation-mediated status epilepticus. Lancet Neurol 2011; 10 (1) 99-108
• 9 Sakuma H, Sugai K, Sasaki M. Acute nonparaneoplastic limbic encephalitis in childhood: a case series in Japan. Pediatr Neurol 2010; 43 (3) 167-172
• 10 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
• 11 Irani SR, Bien CG, Lang B. Autoimmune epilepsies. Curr Opin Neurol 2011; 24 (2) 146-153
• 12 Rosenfeld MR, Dalmau J. Update on paraneoplastic and autoimmune disorders of the central nervous system. Semin Neurol 2010; 30 (3) 320-331
• 13 Vincent A, Irani SR, Lang B. The growing recognition of immunotherapy-responsive seizure disorders with autoantibodies to specific neuronal proteins. Curr Opin Neurol 2010; 23 (2) 144-150
• 14 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
• 15 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
• 16 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
• 17 Kobayashi K, Ouchida M, Okumura A , et al. Genetic seizure susceptibility underlying acute encephalopathies in childhood. Epilepsy Res 2010; 91 (2-3) 143-152
• 18 Nishri D, Blumkin L, Lev D , et al. Hepatic coma culminating in severe brain damage in a child with a SCN1A mutation. Eur J Paediatr Neurol 2010; 14 (5) 456-459
• 19 Wolf NI, Rahman S, Schmitt B , et al. Status epilepticus in children with Alpers' disease caused by POLG1 mutations: EEG and MRI features. Epilepsia 2009; 50 (6) 1596-1607
• 20 Tschampa HJ, Greschus S, Sassen R, Bien CG, Urbach H. Thalamus lesions in chronic and acute seizure disorders. Neuroradiology 2011; 53 (4) 245-254
• 21 Ravizza T, Balosso S, Vezzani A. Inflammation and prevention of epileptogenesis. Neurosci Lett 2011; 497 (3) 223-230
• 22 Finsterer J. Leigh and Leigh-like syndrome in children and adults. Pediatr Neurol 2008; 39 (4) 223-235
• 23 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
• 24 Debray FG, Lambert M, Chevalier I , et al. Long-term outcome and clinical spectrum of 73 pediatric patients with mitochondrial diseases. Pediatrics 2007; 119 (4) 722-733
• 25 Hasselmann O, Blau N, Ramaekers VT, Quadros EV, Sequeira JM, Weissert M. Cerebral folate deficiency and CNS inflammatory markers in Alpers disease. Mol Genet Metab 2010; 99 (1) 58-61
• 26 Suleiman J, Brenner T, Gill D , et al. VGKC antibodies in pediatric encephalitis presenting with status epilepticus. Neurology 2011; 76 (14) 1252-1255
• 27 Akman CI, Patterson MC, Rubinstein A, Herzog R. Limbic encephalitis associated with anti-GAD antibody and common variable immune deficiency. Dev Med Child Neurol 2009; 51 (7) 563-567
• 28 Specchio N, Fusco L, Vigevano F. Acute-onset epilepsy triggered by fever mimicking FIRES (febrile infection-related epilepsy syndrome): the role of protocadherin 19 (PCDH19) gene mutation. Epilepsia 2011; 52 (11) e172 –e175