Antibodies against GluR3 peptides are not specific for Rasmussen's encephalitis but are also present in epilepsy patients with severe, early onset disease and intractable seizures
Introduction
Rasmussen's encephalitis (RE) is a rare progressive form of epilepsy that affects otherwise normal children in the first decade of life Rasmussen et al., 1958, Dulac, 1996. The classic clinical picture is one of severe focal epilepsy with progressive dysfunction of one cerebral hemisphere accompanied by focal neurological signs and cognitive decline. The seizures are refractory to all antiepileptic drugs (Rasmussen and Andermann, 1992). Evidence is accumulating which suggests that RE may be a humoral-mediated autoimmune disease. Thus, epileptic seizures and an inflammatory histopathology of the brain were observed in two rabbits immunized with a portion of the extracellular domain of glutamate receptor 3 (GluR3) fusion protein (Twyman et al., 1995); furthermore, plasma exchange has produced transient improvements in seizure frequency and neurological function in some RE patients Rogers et al., 1994, Andrews et al., 1996, Antozzi et al., 1998. Subsequent studies demonstrated that anti-GluR3 antibodies obtained from GluR3-immunized rabbits promote the in vitro death of cortical neurons by a complement-mediated mechanism (He et al., 1998), and that anti-IgG and anti-membrane attack complex (MAC) antibodies localize on the neuronal cell bodies of sections of cortex resected from RE patients He et al., 1998, Whitney et al., 1999.
However, this emerging picture is complicated by the findings that not all rabbits immunized with the GluR3 fusion protein got sick (Twyman et al., 1995), and that MAC immunoreactivity was present only in a subset of RE patients – those characterized by an active progressive form of RE (Whitney et al., 1999). Furthermore, localized inflammatory reactions have been detected in surgical specimens from some patients who had received temporal lobectomy for refractory epilepsy (McNamara, 1999) raising the prospect of autoimmune involvement in other forms of epilepsy. With regard to RE, there is the challenging conceptual problem as to how autoantibodies might be responsible for progressive destruction of a single cerebral hemisphere.
We carried out a wide-ranging study on the presence of anti-GluR3 antibodies in RE, other forms of epilepsy and other neurological diseases (including autoimmune neurological disorders) to evaluate the specificity and sensitivity of anti-GluR3 antibody testing as a marker for epileptic conditions.
Section snippets
Patients
We studied 11 patients (6 males, 5 females; mean age 11±5 years, range 4–22) with RE from several Italian epilepsy centers. RE was diagnosed in the presence of drug-resistant focal epilepsy, epilepsia partialis continua, evidence of progressive neurological and cognitive deficit and progressive hemispheric atrophy on MRI. Nine of the RE patients underwent surgery, and neuropathological examination confirmed the presence of inflammatory alterations in resected cortical specimens. We also studied
Antibodies against GluR3A and 3B peptides
Scatter plots of individual antibody titers (ODs) at serum dilution 1:200 are shown in Fig. 1 for all patient groups and for healthy controls.
Discussion
Autoantibodies can be markers of disease activity and severity, an aid to disease classification and a guide to therapy, provided the autoantibody assay is sufficiently specific and sensitive and has a sufficiently high predictive value (Leslie et al., 2001). Since GluR3 is a putative antigen in RE (Rogers et al., 1994), we examined a large cohort of patients with this rare condition, and also other forms of epilepsy, to determine whether anti-GluR3 antibodies are diagnostic markers of RE.
Acknowledgements
Authors thank Dr. R. Longhi (Institute of Biocatalysis and Molecular Recognition, CNR, Milan) for the peptide synthesis, Mrs. O. Simoncini for technical assistance, and Don Ward for help with the English. This study was generously supported by a grant from the Pierfranco and Luisa Mariani Foundation, Milan, Italy (R.S.).
References (19)
- et al.
Glutamate receptor GluR3 antibodies and death of cortical cells
Neuron
(1998) - et al.
Autoantibodies to the glutamate receptor kill neurons via activation of the receptor ion channel
J. Autoimmunity
(1999) - et al.
Glutamate receptor antibodies activate a subset of receptors and reveal an agonist binding site
Neuron
(1995) - et al.
Antibodies against β1 and β2 adrenergic receptors in myasthenia gravis
J. Neuroimmunol.
(1998) - et al.
Plasmapheresis in Rasmussen's encephalitis
Neurology
(1996) - et al.
Long-term selective IgG immunoadsorption improves Rasmussen's encephalitis
Neurology
(1998) - et al.
Destruction of neurons by cytotoxic T cells in Rasmussen's encephalitis
J. Neuroimmunol.
(2001) Proposal for revised classification of epilepsies and epileptic syndromes
Epilepsia
(1989)Rasmussen's syndrome
Curr. Opin. Neurol.
(1996)
Cited by (144)
Anti-GluA3 autoantibodies define a new sub-population of frontotemporal lobar degeneration patients with distinct neuropathological features
2024, Brain, Behavior, and ImmunityA case of repeated focal motor seizures as expression of an inflammatory cerebral process with suspected dysimmune etiology
2022, Epilepsy and Behavior ReportsDiagnostic Pathology: Neuropathology
2017, Diagnostic Pathology: NeuropathologyEpilepsy, Immunity and Neuropsychiatric Disorders
2023, Current Neuropharmacology
- 1
Drs. L. Passerini, B. Cippelletti, E. Freri, F. Villani, M. Casazza, L. Angelini (Istituto Nazionale Neurologico “Carlo Besta”, Milan); Dr. G. Gobbi (Ospedale Maggiore, Bologna); Dr. L. Fusco (Ospedale Pediatrico Bambin Gesù, Rome); Drs. A. Tiberti, I. Giordano (Ospedali Civili di Brescia, Brescia); Dr. G. Capovilla (Ospedale di Mantova); Dr. M. Viri (Ospedale Fatebenefratelli, Milan); Dr. B. Dalla Bernardina (Policlinico, Verona); Dr. L. Tassi (Centro Regionale per la Chirurgia dell'Epilessia, Ospedale Niguarda, Milan).