Short Communication

Voltage-Gated Potassium Channels Autoantibodies in a Child with Rasmussen Encephalitis Marie-Aude Spitz1 Fanny Dubois-Teklali2 Laurent Vercueil3 Angela Vincent5 Viviana Oliver6 Christine Bulteau6,7 1 Service de Pédiatrie 1, CHRU Hautepierre, Strasbourg, France 2 Clinique Universitaire de Pédiatrie, CHU Grenoble, Grenoble, France 3 Explorations Fonctionnelles du Système Nerveux, CHU Grenoble,

Cécile Sabourdy3

Frédérique Nugues4

Address for correspondence Marie-Aude Spitz, MD, Service de Pédiatrie 1, CHRU Hautepierre, Avenue de Molière, 67098 Strasbourg Cedex, France (e-mail: [email protected]).

Grenoble, France 4 Département de Radio-pédiatrie, CHU Grenoble, Grenoble, France 5 West Wing and Weatherall Institute of Molecular Medicine, John

Radcliffe Hospital, Oxford, United Kingdom 6 Service de Neurochirurgie Pédiatrique, Fondation Ophtalmologique Rothschild, Paris, France 7 Inserm U1129, Paris, France; University Paris Descartes; PRES

Sorbonne Paris Cité, France ; CEA, Gif sur Yvette, France Neuropediatrics 2014;45:336–340.



► autoimmunity ► child ► epilepsia partialis continua ► immunosuppressive therapy ► Rasmussen encephalitis

received April 6, 2013 accepted after revision May 21, 2014 published online July 25, 2014

Rasmussen encephalitis (RE) is a severe epileptic and inflammatory encephalopathy of unknown etiology, responsible for focal neurological signs and cognitive decline. The current leading hypothesis suggests a sequence of immune reactions induced by an indeterminate factor. This sequence is thought to be responsible for the production of autoantibody-mediated central nervous system degeneration. However, these autoantibodies are not specific to the disease and not all patients present with them. We report the case of a 4-year-old girl suffering from RE displaying some atypical features such as fast evolution and seizures of left parietal onset refractory to several antiepileptics, intravenous immunoglobulins, and corticosteroids. Serum autoantibodies directed against voltage-gated potassium channels (VGKC) were evidenced at 739 pM, a finding never previously reported in children. This screening was performed because of an increased signal in the temporolimbic areas on brain magnetic resonance imaging, which was similar to what is observed during limbic encephalitis. The patient experienced epilepsia partialis continua with progressive right hemiplegia and aphasia. She underwent left hemispherotomy at the age of 5.5 years after which she became seizure free with great cognitive improvement. First described in adults, VGKC autoantibodies have been recently described in children with various neurological manifestations. The implication of VGKC autoantibodies in RE is a new observation and opens up new physiopathological and therapeutic avenues of investigation.

© 2014 Georg Thieme Verlag KG Stuttgart · New York

DOI 10.1055/s-0034-1383822. ISSN 0174-304X.

This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.


Introduction Rasmussen encephalitis (RE) is a rare epileptic and inflammatory pathology with progressive dysfunction of one cerebral hemisphere, characterized by refractory focal seizures, often associated with epilepsia partialis continua, progressive unilateral motor defect and cognitive decline, slow EEG activity over the contralateral hemisphere, focal white matter hyperintensity, and insular cortical atrophy on neuroimaging.1 There is evidence of an autoimmune process in the pathogenesis of RE.1 The current leading hypothesis suggests that an indeterminate factor triggers a chain of immune reactions through the production of autoantibodies. Antibody-mediated central nervous system degeneration has been reported to be responsible for cerebral necrosis; antibodies against Glu-R3 (subunit 3 of the ionotropic glutamate receptor) were the first identified.2 Their essential role in the disease is disputed. We report the case of an aggressive RE, in whom a high level of autoantibodies against voltage-gated potassium channels (VGKC) was detected in the serum. VGKC complex antibodies have been reported in a range of central and peripheral neurologic disorders, but never in RE.

Observation This 4-year-old girl developed partial onset seizures beginning with jerks on the right cheek followed by right leg

Spitz et al.

hypertonia and myoclonus causing her to fall. Her brother had febrile seizure but her personal and family history was otherwise unremarkable. The evolution was marked by bilateralization of seizures, rapidly followed by epilepsia partialis continua and an enrichment of seizure types, refractory to oxcarbazepine, topiramate, and valproate. The first electroencephalogram (EEG) showed normal interictal background activity and focal spikes over the vertex and left cerebral hemisphere, as well as left frontal central and vertex ictal discharge (►Fig. 1); magnetic resonance imaging (MRI) revealed left hippocampus T2 hyperintensity and enlargement (►Fig. 2). Neuropsychological testing at the age of 5 years revealed average total intellectual quotient (TIQ ¼ 105) on the Weschler scale (WPPSI-III) with dissociation between verbal intellectual quotient (IQ) (96) and performance IQ (111). Later, MRI showed T2 hyperintensity in the left anterior temporal, hippocampus, and insula regions. Cerebrospinal fluid analysis pointed out an oligoclonal banding immunoglobulin G (IgG), which was absent in the serum. We hypothesized RE despite the fast course and nonspecific MRI images. Despite antiepileptic adjustment, corticosteroids, intravenous immunoglobulins, intensification of rehabilitation and ketogenic diet, she developed permanent right hemicorporal deficiency and global cognitive deterioration with aphasia 18 months after the first seizure. The EEG showed left-sided slow activity with synchronous spikes over the vertex and left

Fig. 1 (a) Interictal electroencephalogram, longitudinal set-up: rhythmic spikes on vertex and central part; (b) longitudinal set-up: seizure (clonic jerks of the right arm on the electromyogram). Neuropediatrics

Vol. 45

No. 5/2014


This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.

VGKC Autoantibodies and Rasmussen Encephalitis

VGKC Autoantibodies and Rasmussen Encephalitis

Spitz et al.

Fig. 2 Brain magnetic resonance imaging (MRI) frontal sections (a) FLAIR: left hippocampus hyperintensity; insula hyperintensity, and enlargement. (b) T2 sequence: progressive predominant left hemispheric atrophy (4 months after the first MRI). (c) After hemispherotomy: left hemispheric atrophy.

central regions and later a diffusion over the entire left hemisphere. These spikes diffused over the right hemisphere but there were no independent spikes and no contralateral focus. MRI demonstrated a hyperintense T2/fluid-attenuated inversion recovery (FLAIR) bilateral cortical and subcortical signal in frontal, rolandic and prerolandic regions, and in the middle and posterior parts of the cingular gyrus. Progressively, a predominant left hemisphere atrophy was observed on successive MRIs. Biological tests disclosed no signs of metabolic encephalopathy, including mitochondrial cytopathy (tested with amino acid chromatography in blood and urine, chromatography urinary organic acids, lactate/pyruvate ratio in blood and CSF). Thyroid hormone titers were within normal limits, thyroid antibodies, and viral serologies (cytomegalovirus, Epstein–Barr virus, and herpes simplex virus) were negative, and plasma protein distribution was normal. Limbic encephalitis was suspected and a search for paraneoplastic antibodies (Hu, Ri, Yo, CV2, amphiphysin, and MA2) was negative. However, the value of serum autoantibodies against VGKC, tested because the initial MRI brain images were similar to those of limbic encephalitis, was elevated at 739 pM (range, 0–1:00 pM). Stereo-EEG (SEEG) was performed with depth electrodes exploring the left parietal-centro-insular areas. Ictal discharges started in the motor opercule and the whole central and precentral regions, but some abnormalities also diffused sometimes over parietal regions with frontal and central predominance. It was not possible to find a focal epileptogenic zone as all EEG abnormalities were wider than the area explored by depth electrodes. She underwent left hemispherotomy at the age of 5.5 years, which involves the complete surgical disconnection of the pathological hemisphere and avoids the late complications of anatomical hemispherectomy. The pathology report exhibited cortical inflammation with lymphocyte invasion. She became seizure-free after surgery and antiepileptic drugs were discontinued. She presented right hemiparesis and hemianopsia but was able to walk alone 4 months after surgery. Neuropsychological assessment at 8.5 years exhibited a normal IQ on the Weschler scale (WISC-IV) with discrepancy between verbal (108) and nonverbal IQs (84) along with subnormal working memory (79) and speed Neuropediatrics

Vol. 45

No. 5/2014

treatment (73). She went back to normal school where she received specially adapted tuition and rehabilitation (speech therapy and physiotherapy). The Achenbach scale did not show any behavioral disorders. Schooling assessment pointed out distractibility and moderate reading abilities. Postoperative MRI demonstrated progressive atrophy (►Fig. 2).

Discussion The diagnosis of RE is based on pharmacoresistant partial motor seizures often associated with epilepsia partialis continua and progressive hemicorporal motor decline; unilateral and progressive deterioration of background activity, multifocal ictal and interictal periodic spike activity on one hemisphere; cortical hyperintensity on T2/FLAIR-weighted cerebral MRI images, occasionally with focal cortical edema and later unilateral cortical atrophy.2 There is no specific biological marker in RE, but oligoclonal banding IgG in CSF and several autoantibodies have been described in previous reports. In the present report, RE displayed atypical clinical and focal EEG features such as fast evolution with epilepsia partialis continua four months after the first symptoms and left centro-parietal seizures respectively. Only a small piece of the frontal lobe can be analyzed with this type of surgical procedure involving hemispheric disconnection.3 The area of brain tissue analyzed was determined by the route of the surgical technique, rather than by abnormalities on the MRI. The pathology report exhibited cortical inflammation with lymphocyte invasion, in favor of RE. Postoperative MRI exhibited progressive left sided atrophy of the whole hemisphere which is also consistent with the diagnosis of RE. Progressive atrophy of the affected hemisphere is specific of RE and continues after hemispherotomy because surgery does not cure the inflammatory process. In contrast, there is no progressive atrophy after hemispherotomy in the other three groups of patients (vascular sequelae, hemispheric Sturge–Weber syndrome, and hemispheric cortical dysplasia) who are candidates for hemispheric disconnection.4 VGKC autoantibodies have been reported in a large spectrum of neurological disorders in adults5 including

This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.


VGKC Autoantibodies and Rasmussen Encephalitis


however, a progressive independent left hemispheric atrophy, suggesting that, although atypical, our patient did, in fact, have RE. We report the first case of RE involving VGKC autoantibodies and this has new physiopathological and therapeutic implications. Our case has not responded to immunosuppressive therapy despite the presence of VGKC autoantibodies. Further studies and evaluations are required and we suggest that anti-VGKC be tested in children with a clinical picture of RE to confirm their implication in the disease.

Conclusion There is evidence of an autoimmune component in the pathogenesis of RE. Glu-R3 antibodies are not specific to the disease and are not present in the sera of all patients. Other autoantibodies are certainly involved in RE. We reported the case of a 4-year-old girl suffering from RE with a high level of VGKC autoantibodies. The involvement of these autoantibodies in our case is unclear. It would be interesting to test these autoantibodies in children presenting a typical clinical picture of RE.

Acknowledgments The authors thank Dr. O. Delalande (Service de Neurochirurgie Pédiatrique, Fondation Ophtalmologique A. de Rothschild, Paris) who performed the left hemispherotomy.

Conflicts of Interest None of the authors has any conflict of interest to disclose.

References 1 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 Varadkar S, Bien CG, Kruse CA, et al. Rasmussen’s encephalitis: clinical features, pathobiology, and treatment advances. Lancet Neurol 2014;13(2):195–205 Delalande O, Bulteau C, Dellatolas G, et al. Vertical parasagittal hemispherotomy: surgical procedures and clinical long-term outcomes in a population of 83 children. Neurosurgery 2007;60(2, Suppl 1):ONS19–ONS32, discussion ONS32 Bordonné C, Delalande O, Dorfmuller G, Héran F. CT and MR brain imaging following hemispherotomy [in French]. J Neuroradiol 2011;38(1):68 Newsom-Davis J, Buckley C, Clover L, et al. Autoimmune disorders of neuronal potassium channels. Ann N Y Acad Sci 2003;998: 202–210 Vincent A, Buckley C, Schott JM, et al. Potassium channel antibodyassociated encephalopathy: a potentially immunotherapy-responsive form of limbic encephalitis. Brain 2004;127(Pt 3): 701–712 Neuropediatrics

Vol. 45

No. 5/2014

This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.

nonparaneoplastic limbic encephalitis responding to immunosuppressive therapy.6 These autoantibodies were tested in our case because of initial MRI brain images showing hippocampal and temporal lesions (an increased signal in temporolimbic areas), similar to limbic encephalitis lesions. During the initial phase of RE, an enlargement of the frontal, temporal, and insular cortex can usually be seen, and T2-weighted and FLAIR MRI sequences show hyperintensity in these regions; in rare cases lesions can involve temporal regions and hippocampus exclusively. Secondarily, there is atrophy of these regions.7 Recently, limbic encephalitis associated with VGKC autoantibodies has been reported in children, with variable but largely unfavorable outcomes after immunosuppressive therapy.8 In the adult population,9 it was shown that most of these autoantibodies bind to leucine-rich gliomainactivated 1 and contactin-associated protein 2 belonging to the VGKC complex, but this was not demonstrated in children.8 Studies reporting autoimmune mechanisms involving VGKC autoantibodies in children are increasing. These autoantibodies have been described in children with encephalitis presenting with status epilepticus, not treated with immunosuppressants, most of whom had a poor outcome10; in children with various neurological manifestations including one with early onset symptomatic generalized epilepsy associated with mesiotemporal MRI changes11; in a child with early-onset epileptic encephalopathy and infantile spasms partially responsive to steroid therapy9; and in a boy with fever-induced refractory epileptic encephalopathy in school age children in which there was a positive clinical response to immunomodulation in the early phase. 12 As previously mentioned, RE is an encephalopathy with unknown etiology. The current leading hypothesis suggests a chain of immune reactions induced by an indeterminate factor. This factor is believed to first activate cytotoxic T lymphocyte cells responsible for the initial neuronal lesions and the production of autoantibodies. Among these antibodies, anti-Glu-R3 have been implicated in cortex destruction with a massive necrosis of one cerebral hemisphere.1 Their presence was not confirmed in all the cases of RE2 and other autoantibodies such as anti–Glu-R2, were present in the sera of some patients suffering from RE.2 RE is a clinical and radiological syndrome and autoantibodies against Glu-R3 were not checked in our case. We suggest that VGKC autoantibodies could be responsible for the atypical clinical and EEG presentation of our case: left unilobar parietal rather than hemispheric epilepsy at the beginning, early seizure onset, as well as fast evolution. VGKC antibodies are directed against molecules on neuronal membranes and have been mainly reported in limbic encephalitis; some patients show characteristic faciobrachial dystonic seizures before developing temporal lobe seizures.9 MRI images in our case are also atypical, showing bihemispheric abnormalities. A possible hypothesis is an atypical onset of autoimmune encephalitis secondary to VGKC autoantibody autoimmunity in RE. Pre- and postsurgery evolution shows,

Spitz et al.

VGKC Autoantibodies and Rasmussen Encephalitis

Spitz et al.

7 Chiapparini L, Granata T, Farina L, et al. Diagnostic imaging in 13

10 Suleiman J, Brenner T, Gill D, et al. VGKC antibodies in pediatric

cases of Rasmussen’s encephalitis: can early MRI suggest the diagnosis? Neuroradiology 2003;45(3):171–183 8 Haberlandt E, Bast T, Ebner A, et al. Limbic encephalitis in children and adolescents. Arch Dis Child 2011;96(2):186–191 9 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

encephalitis presenting with status epilepticus. Neurology 2011; 76(14):1252–1255 11 Dhamija R, Renaud DL, Pittock SJ, et al. Neuronal voltage-gated potassium channel complex autoimmunity in children. Pediatr Neurol 2011;44(4):275–281 12 Illingworth MA, Hanrahan D, Anderson CE, et al. Elevated VGKCcomplex antibodies in a boy with fever-induced refractory epileptic encephalopathy in school-age children (FIRES). Dev Med Child Neurol 2011;53(11):1053–1057

This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.



Vol. 45

No. 5/2014

Copyright of Neuropediatrics is the property of Georg Thieme Verlag Stuttgart and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.

Voltage-gated potassium channels autoantibodies in a child with rasmussen encephalitis.

Rasmussen encephalitis (RE) is a severe epileptic and inflammatory encephalopathy of unknown etiology, responsible for focal neurological signs and co...
253KB Sizes 1 Downloads 4 Views

Recommend Documents

Exceptional verbal intelligence after hemispherotomy in a child with Rasmussen encephalitis.
We report a longitudinal case study of a left-handed girl who underwent left hemispherotomy at 7 years for Rasmussen encephalitis (RE). Presurgical evaluation showed mild hemiparesis, no visual defect, and light neuropsychological impairment with sho

Upregulation of adenosine kinase in Rasmussen encephalitis.
Rasmussen encephalitis (RE) is a rare neurologic disorder of childhood characterized by unihemispheric inflammation, progressive neurologic deficits, and intractable focal epilepsy. The pathogenesis of RE is still enigmatic. Adenosine is a key endoge

Rasmussen encephalitis with dual pathology in a patient without seizures: case report and literature review.
Rasmussen encephalitis without seizures is rare. We report a case of Rasmussen encephalitis and cortical dysplasia without epilepsy as well as describe the imaging, pathology, and clinical course and review the literature to investigate whether this

"Autoimmune Epilepsy": Encephalitis With Autoantibodies for Epileptologists.
Autoimmune encephalitides may account for epilepsies of so far unknown cause. These "autoimmune epilepsies" may respond well to immunotherapy. More than a dozen autoantibodies have been found with this constellation; therefore, broad autoantibody tes

Evidence for Resident Memory T cells in Rasmussen Encephalitis.
Investigators from University of California Los Angeles studied the presence of different T cell subset population in the brain tissue of 7 patients with Rasmussen encephalitis, a rare neuroinflammatory disorder characterized by intractable seizures

Targeting potassium channels in cancer.
Potassium channels are pore-forming transmembrane proteins that regulate a multitude of biological processes by controlling potassium flow across cell membranes. Aberrant potassium channel functions contribute to diseases such as epilepsy, cardiac ar

Structure of potassium channels.
Potassium channels ubiquitously exist in nearly all kingdoms of life and perform diverse but important functions. Since the first atomic structure of a prokaryotic potassium channel (KcsA, a channel from Streptomyces lividans) was determined, tremend