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

Andreas van Baalen; Martin Häusler; Barbara Plecko-Startinig; Jurgis Strautmanis; Stefan Vlaho; Boris Gebhardt; Axel Rohr; Angela Abicht; Gerhard Kluger; Ulrich Stephani; Christian Probst; Angela Vincent; Christian G. Bien

doi:10.1055/s-0032-1323848

Neuropediatrics, Table of Contents

Neuropediatrics 2012; 43(04): 209-216
DOI: 10.1055/s-0032-1323848

Short Communication

Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

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

Andreas van Baalen

¹Department of Neuropediatrics, University Medical Center Schleswig-Holstein, Christian-Albrechts-Universität zu Kiel, Kiel, Germany

,

Martin Häusler

²Department of Pediatrics, University Hospital, RWTH Aachen, Aachen, Germany

,

Barbara Plecko-Startinig

³Department of Pediatrics and Adolescence Medicine, Medical University of Graz, Graz, Austria

,

Jurgis Strautmanis

⁴University Clinical Children's Hospital, Department of Neurology and Neurosurgery, Riga, Latvia

,

Stefan Vlaho

⁵University Children's Hospital, Johann Wolfgang Goethe-University, Frankfurt, Germany

,

Boris Gebhardt

⁶MVZ Gelnhausen, Gelnhausen, Germany

,

Axel Rohr

⁷Institute of Neuroradiology, University Medical Center Schleswig-Holstein, Christian-Albrechts-Universität zu Kiel, Kiel, Germany

,

Angela Abicht

⁸Medical Genetic Centre, Munich, Germany

,

Gerhard Kluger

⁹Neuropediatric Clinic and Clinic for Neurorehabilitation, Epilepsy Center for Children and Adolescents, Vogtareuth, Germany

,

Ulrich Stephani

¹Department of Neuropediatrics, University Medical Center Schleswig-Holstein, Christian-Albrechts-Universität zu Kiel, Kiel, Germany

,

Christian Probst

¹⁰Institute of Experimental Immunology, Euroimmun, Lübeck, Germany

,

Angela Vincent

¹¹Nuffield Department of Clinical Neurosciences, John Radcliffe Hospital, Oxford OX3 0DU, United Kingdom

,

Christian G. Bien

¹²Epilepsy Center Bethel, Krankenhaus Mara, Bielefeld, Germany

› Author Affiliations

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

Full Text

References

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