This article appeared in a journal published by Elsevier. The attached copy is furnished to the author for internal non-commercial research and education use, including for instruction at the authors institution and sharing with colleagues. Other uses, including reproduction and distribution, or selling or licensing copies, or posting to personal, institutional or third party websites are prohibited. In most cases authors are permitted to post their version of the article (e.g. in Word or Tex form) to their personal website or institutional repository. Authors requiring further information regarding Elsevier’s archiving and manuscript policies are encouraged to visit: http://www.elsevier.com/copyright
Author's personal copy Epilepsy Research (2010) 90, 295—299
journal homepage: www.elsevier.com/locate/epilepsyres
SHORT COMMUNICATION
Beneficial effect of epilepsy surgery in a case of childhood non-paraneoplastic limbic encephalitis Angelika Muehlebner a,b, Gudrun Groeppel a, Gerald Pahs a, Johannes A. Hainfellner b, Daniela Prayer c, Thomas Czech d, Martha Feucht a,∗ a
Department of Pediatrics, Medical University Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria Institute of Neurology, Medical University Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria c Department of Radiology, Division of Neuroradiology, Medical University Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria d Department of Neurosurgery, Medical University Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria b
Received 28 February 2010; received in revised form 24 April 2010; accepted 16 May 2010 Available online 12 June 2010
KEYWORDS Mesial temporal lobe epilepsy; Drug-resistance; Unilateral hippocampal sclerosis; Epilepsy surgery; Limbic encephalitis
Summary This 15-year-old girl had subacute onset of secondary generalized seizures, confusion, and subsequent memory decline. MRI showed bilateral hippocampal swelling progressing to unilateral mesial temporal sclerosis (MTS) within 12 months. Epilepsy surgery was performed, and laboratory data were consistent with non-paraneoplastic limbic encephalitis. 18 months after epilepsy surgery, the patient is seizure-free with stable cognitive functions. © 2010 Elsevier B.V. All rights reserved.
Introduction Autoimmune limbic encephalitis (LE) is an inflammatory disease primarily restricted to the hippocampus. Clinical characteristics include subacute onset, profound cognitive impairment (especially memory decline), psychiatric disorders, and epileptic (usually complex partial) seizures (Bien and Elger, 2007). Serial brain MRIs have shown uni- or bilateral swollen temporomesial structures at disease onset and
∗ Corresponding author. Tel.: +43 1 40400 3385; fax: +43 1 40400 2277. E-mail address:
[email protected] (M. Feucht).
progressive temporomesial sclerosis/atrophy (Urbach et al., 2006). Histopathology shows medial temporal lobe inflammation, i.e. infiltrating round cells (T-lymphocytes) and activated microglial cells, which sometimes form nodules. LE can occur as a paraneoplastic phenomenon (PNLE) (Gultekin et al., 2000) associated with onconeuronal antibodies to intracellular antigens, mainly Hu, CRMP5/CV2, Ma2, amphiphysin in patients with small cell lung cancer (SCLC), neuronal surface antibodies to voltage-gated potassium channel (VGKC) in and glutamic acid decarboxylase (GAD) in combination with SCLC or thymoma and antibodies to N-methyl-D-aspartate receptor (NMDA-R) together with ovarian teratoma (Dalmau and Rosenfeld, 2008). Removal of the tumour seems to improve neurological outcome (Dalmau
0920-1211/$ — see front matter © 2010 Elsevier B.V. All rights reserved. doi:10.1016/j.eplepsyres.2010.05.009
Author's personal copy 296 and Rosenfeld, 2008). Other causes of LE may be direct invasion of a virus, usually human herpesvirus (HHV)-6 (Theodore et al., 2008) and autoimmune processes without tumour association. Antibodies to specific neuronal cell-surface membrane proteins have been discovered in different forms of non-paraneoplastic limbic encephalitis (NPLE), in 18% of 53 patients anti-VGKC (Buckley et al., 2001; Malter et al., 2010), in 17% of 53 patients anti-GAD (Mata et al., 2008; Malter et al., 2010), in 7.5% of 53 patients anti-NMDA-R (Dalmau et al., 2008; Malter et al., 2010) antibodies. However, in about 20—55% of NPLE, no such auto-antibodies have been found (Graus et al., 2008; Malter et al., 2010). NPLE do not show a good response to conventional antiepileptic drugs (AEDs), but respond to immunotherapies. Immunosuppression is therefore widely considered as first-line treatment in these patients (Bataller et al., 2007). NPLE has been identified almost exclusively in adults, whereas most paediatric-onset LE seem to be paraneoplastic (Florance et al., 2009). We report a 15-year-old girl with NPLE and favourable outcome after epilepsy surgery.
Case This healthy 15-year-old girl presented with memory and concentration problems, followed by episodes of nausea, epigastric sensations, confusion and blurred language since
A. Muehlebner et al. January 2007. The patient was otherwise healthy, with no medical problems in the past. Development had been normal. She attended high school with recent decline in academic performance. Family history was unremarkable. In July 2007, she was hospitalized because of two secondary generalized tonic—clonic seizures (GTCS). Clinical examinations at admission were normal, as were routine blood tests. Initial evaluation did not suggest neoplastic, toxic or metabolic aetiology. Virus-PCR (including adeno-, coxsackie-, enteroviruses, measles, mumps, rubella, influenza A + B, JC virus, HSV 1 + 2, EBV, CMV, VZV and HHV 6 + 7) and diagnostic work-up for bacterial or fungal cause of infection were negative. Immunological parameters including ASLO, anti-DNA, streptococcal DNAse, ANA, ANCA and Lupus serology were normal. Cerebrospinal fluid (CSF) showed 6 cells/l (primarily lymphocytes) and normal protein content. Neuropsychological testing revealed normal full-IQ, but deficits in verbal and non-verbal episodic memory. Magnetic resonance imaging (MRI) displayed bilateral abnormal hyperintense signals in the mesial temporal areas on T2/FLAIR images, more prominent on the left side (Fig. 1A and B). FDG-positron-emission-tomography (PET) showed reduced tracer-uptake of the left mesiotemporal region. Diagnosis of LE was based on the features of (1) ‘‘limbic’’ signs and symptoms for ≤5 years (impaired recent memory,
Figure 1 (A—D) Coronary T2 and axial FLAIR MRI sequences showing bilateral signal enhancement and swelling of the mesial temporal lobe, whereas hyperintensity was more distinct on the left side (A, July 2007; B, August 2007). Decrease of swelling, beginning of hippocampal atrophy (C, October 2007). Left hippocampal atrophy with signal increase on FLAIR sequence indicating hippocampal sclerosis (D, March 2008).
Author's personal copy Beneficial effect of epilepsy surgery in a case of childhood non-paraneoplastic limbic encephalitis temporal lobe seizures and affective abnormalities) and (2) prototypical MRI evidence of mediotemporal encephalitis. Paraneoplastic aetiologies were excluded following the Bonn protocol for tumour search in limbic encephalitis (Malter et al., 2010) including abdominal ultrasound examination and computer tomography scan with contrast enhancement of the chest and abdominal region, gynaecological examination, and serological tests for both cancer-specific (CEA, CA125 and CA 19-9) and tissue-specific tumour markers (AFP, beta-HCG, Thyroglobulin and neuronspecific Enolase). All results were negative and therefore we the LE was classified non-paraneoplastic. For autoantibody screening serum was analyzed for anti-Yo, Hu. Ri and Ma antibodies (immunoblot and indirect immunofluorescence), anti-GAD antibodies at the Medical University of Vienna and sent to Vincent A (University of Oxford, Weatherall Institute of Molecular Medicine) for antibodies against VGKC and NMDA-R. Results were negative. NPLE was diagnosed and treatment with both 1 g of methylprednisolone/day for 3 days and levetirazetame was initiated. However, a few month later complex-partial seizures occurred with increasing frequency (1—2/day) despite high doses of levetiracetame, carbamazepine, oxcarbazepine, topiramate and clobazame. School performance declined further and neuropsychological re-evaluation in March 2008 showed cognitive deterioration. MRI scans 3 and 8 months after disease-onset (October 2007 and March 2008), demonstrated development of left hippocampal atrophy (HA) and T2/FLAIR signal increase indicating hippocampal sclerosis (HS) (Fig. 1C and D). EEGvideo-monitoring from May 2008 showed interictal spikes and seizure onset in the left sphenoidal electrode (Fig. 2A). Left anterior 2/3 temporal-lobectomy was performed on July 25th 2008. The resected specimen, divided into several parts (anterior, middle and posterior part of the hippocampus as well as the amygdala) were carefully orientated, trimmed and sectioned in the plane perpendicular to its longitudinal axis. The specimens were routinely processed for histopathology. In addition to hematoxylin and eosin (HE) stains, immunohistochemistry was performed. We stained tissue sections with antibodies against CD 3 (Neomarkers, Thermo Fisher Scientific Inc, Fremont, CA, USA, 1:100), CD 4 (Novocastra, Leica Microsystem, Germany, 1:10), CD 8 (Dako, Glostrup, Denmark, 1:100), CD 20 (Dako, Glostrup, Denmark, 1:200), CD 45 RO (OPD 4, Dako, Glostrup, Denmark, 1:100), CD 68 (Dako, Glostrup, Denmark, 1:1000), Caspase 3 (Cell Signalling Technology Inc, Danvers, MA, USA, 1:100) and Caspase 9 (Chemicon, 1:20). For antigen retrieval (except CD 4), the slides were pretreated in a microwave oven for 10 min in 10 mM citric acid buffer at pH 6. For IgG-staining 4 m thick sections were deparaffinized in xylene. Endogenous peroxidase was blocked by incubation in 0.03% hydrogen peroxide for 30 min. The sections were rehydrated through a descending ethanol series and rinsed in distilled water. The slides were heated in 10 mM citrate buffer. Slides were then exposed to 3% milk powder in phosphate buffered saline (PBS) for 30 min at room temperature to reduce non-specific background. The slides were washed with PBS several times and incubated with patient’s serum 1:1000 in 1.5% milk powder in PBS at 4 ◦ C overnight. The sections were then washed in PBS and incubated with biotinylated rabbit anti-human IgG secondary
297
antibody 1:1000 in 1.5% milk powder in PBS for 2 h at room temperature. All the sections were counterstained with Meyer’s hematoxylin, dehydrated, and coverslipped. Negative controls were performed by omitting the primary antibody, by using irrelevant isotype control antibodies, and by using age-matched control cases from patients without recurring seizures. For immunological studies routine screening procedures for identification of serum auto-antibodies with indirect immunofluorescence were used. Rat cerebellum/brainstem frozen sections served as substrate, FITC-conjugated rabbit anti-human IgG as conjugate. For visualization of antibody binding a rabbit anti-human secondary antibody, which was conjugated with horse raddish peroxidase, was used. All signals were detected with the EnVision kit (Dakocytomation K5007, Glostrup, Denmark). The low-power microscopic findings of the hippocampus showed a typical pattern of HA/HS (Fig. 2B), characterized by severe loss of neurons and gliosis of the CA 1 sector of the pyramidal cell layer. The other subfields showed fewer changes. The granular neurons of the dentate gyrus were slightly dispersed. The high-power view showed chronic inflammation and infiltration with macrophages (Fig. 2C). Especially in the CA1 subfield, the infiltrates were composed of CD 3+ CD 8+ T-lymphocytes (more than 8 cells/high power field) and CD 68+ macrophages (Fig 2D and E). There was also microglial activation detectable. Positive signals with Caspase 3 and 9 were not retrieved. Results of immunohistochemical staining of patient’s brain for IgG were not different from age-matched controls. 18 months after surgery, the patient is still seizurefree on stable AED treatment with lacosamide. MRI scans 3 and 12 months after surgery showed a normal post-surgical situation without signal alteration of the right mesial structures. Neuropsychological testing in November 2008 and July 2009 revealed significant improvement of general intellectual performance, long-term memory, serial reproduction and visual-motoric coordination. Follow-up tumour screening remained negative.
Discussion Clinical outcome data on non-paraneoplastic limbic encephalitis in paediatric patients are rare. We report a case of paediatric-onset NPLE, subsequent unilateral HA/HS and drug-resistant TLE as previously described in adult patients (Bien et al., 2007). Rapid evolution of hippocampal swelling into atrophy and sclerosis of the mesial structures 3—8 months after disease-onset is demonstrated by serial MRI. As the girl never experienced convulsive status epilepticus (SE) during the disease course, it seems unlikely that these findings were the consequence of acute seizure activity (Nohria et al., 1994; Tien and Felsberg, 1995; Wieshmann et al., 1997). Further (and in contrast to our case where histopathology showed chronic inflammation consistent with LE), significant inflammation was not reported in surgically resected hippocampal specimen of SE patients and brain biopsies performed in seven children with febrile infection-related epilepsy syndrome (FIRES) showed gliosis but no inflammation (Van Baalen et al., 2010). Despite intensive antibody search and detailed tissue
Author's personal copy 298
A. Muehlebner et al.
Figure 2 (A) Interictal EEG with sharp slow waves left temporal. (B—E) Microscopic findings. Ammon’s horn sclerosis with lesioning of the CA1 subfield (B, NeuN, 12.5×). Perivascular infiltrates composed of lymphocytes and macrophages (arrowheads) (C, H—E, 200×). Immunohistochemical labelling of macrophages in the CA 1 subfield (D, CD 68, 200×, brown label). CD 8+ T-lymphocytes infiltrating the lesional zone (more than 8 cells/high power field) in the CA 1 subfield (E, CD 8, arrows, 200×, brown label). (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of the article.)
analysis, the underlying cause of LE in our patient remains unclear. However, antibodies may have been present earlier and already disappeared at the time of testing (Jarius et al., 2008). Long-term immunosuppression, which is widely considered the first-line treatment of LE (independent of clinical
symptomatology and autoantibody findings), was not administered in our case, because response is variable and patients with antibodies to cell-membrane antigens usually respond better (Bataller et al., 2007). Further, we found only a few case reports and one study addressing immunotherapy in paediatric NPLE (Kröll-Seger et al., 2009; Akman et al.,
Author's personal copy Beneficial effect of epilepsy surgery in a case of childhood non-paraneoplastic limbic encephalitis 2009; Florance et al., 2009). Finally, our patient rapidly developed unilateral AHS/TLE, which made the girl an ideal candidate for epilepsy surgery. Although long-term prognosis still remains uncertain excellent seizure control and favourable cognitive outcome have been achieved for now 18 months. This so far favourable outcome indicates that — despite the presumed progressive nature of LE — epilepsy surgery may be a treatment option in some of these patients.
Disclosure The authors declare no conflicts of interest associated with this manuscript. Full consent for publication of material relating to them in a peer reviewed journal was obtained from the patient and her mother (legal representative). We confirm that we have read the Journal’s position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.
Acknowledgements Financial support for this project exclusively comes from the Anniversary Fund of the Central Bank of the Republic of Austria (awarded to Dr Feucht), Grant Number ÖNB-12036. This study is part of the doctoral thesis project ‘‘Pediatric Epilepsy Surgery — Predictors of (un)favourable Outcome’’, see also www.meduniwien.ac.at/clins. We thank Dr. Bien (University of Bonn, Medical Centre) for critical discussion, the technical staff of the Vienna Paediatric Epilepsy Monitoring Unit for their support and Dr. Höftberger as well as I. Leisser for perfect technical assistance.
References Akman, C.I., Patterson, M.C., Rubinstein, A., Herzog, R., 2009. Limbic encephalitis associated with anti-GAD antibody and common variable immune deficiency. Dev. Med. Child Neurol. 51, 563—567. Bataller, L., Kleopa, K.A., Wu, G.F., Rossi, J.E., Rosenfeld, M.R., Dalmau, J., 2007. Autoimmune limbic encephalitis in 39 patients: immunophenotypes and outcomes. J. Neurol. Neurosurg. Psychiatry 78, 381—385. Bien, C.G., Elger, C.E., 2007. Limbic encephalitis: a cause of temporal lobe epilepsy with onset in adult life. Epilepsy Behav. 10, 529—538. Bien, C.G., Urbach, H., Schramm, J., Soeder, B.M., Becker, A.J., Voltz, R., Vincent, A., Elger, C.E., 2007. Limbic encephalitis as a precipitating event in adult-onset temporal lobe epilepsy. Neurology 69, 1236—1244. Buckley, C., Oger, J., Clover, L., Tuzun, E., Carpenter, K., Jackson, M., Vincent, A., 2001. Potassium channel antibodies in two patients with reversible limbic encephalitis. Ann. Neurol. 50, 73—78. Dalmau, J., Rosenfeld, M.R., 2008. Paraneoplastic syndromes of the CNS. Lancet Neurol. 7, 327—340.
299
Dalmau, J., Gleichman, A.J., Hughes, E.G., Rossi, J.E., Peng, X., Lai, M., Dessain, S.K., Rosenfeld, M.R., Balice-Gordon, R., Lynch, D.R., 2008. Anti-NMDA-receptor encephalitis: case series and analysis of the effects of antibodies. Lancet Neurol. 7, 1091—1098. Florance, N.R., Davis, R.L., Lam, C., Szperka, C., Zhou, L., Ahmad, S., Campen, C.J., Moss, H., Peter, N., Gleichman, A.J., Glaser, C.A., Lynch, D.R., Rosenfeld, M.R., Damlau, J., 2009. Anti-Nmethyl-D-aspartate receptor (NMDAR) encephalitis in children and adolescents. Ann. Neurol. 66, 11—18. Graus, F., Saiz, A., Lai, M., Bruna, J., Lopez, F., Sabater, L., Blanco, Y., Rey, M.J., Ribalta, T., Dalmau, J., 2008. Neuronal surface antigen antibodies in limbic encephalitis: clinical-immunologic associations. Neurology 71, 930—936. Gultekin, S.H., Rosenfeld, M.R., Voltz, R., Eichen, J., Posner, J.B., Dalmau, J., 2000. Paraneoplastic limbic encephalitis: neurological symptoms, immunological findings and tumour association in 50 patients. Brain 123, 1481—1494. Jarius, S., Hoffmann, L.A., Stich, O., Clover, L., Rauer, S., Vincent, A., Voltz, R., 2008. Relative frequency of VGKC and ‘‘classical’’ paraneoplastic antibodies in patients with limbic encephalitis. J Neurol 255, 1100—1101. Kröll-Seger, J., Bien, C.G., Huppertz, H.J., 2009. Nonparaneoplastic limbic encephalitis associated with antibodies to potassium channels leading to bilateral hippocampal sclerosis in a pre-pubertal girl. Epileptic Disord. 11, 54—59. Malter, M., Urbach, H., Vincent, A., Bien, C.G., 2010. Antibodies to glutamic acid decarboxylase define a form of limbic encephalitis. Ann. Neurol. 67, 470—478. Mata, S., Muscas, G.C., Naldi, I., Rosati, E., Paladini, S., Cruciatti, B., Bisulli, F., Paganini, M., Mazzi, G., Sorbi, S., Tinuper, P., 2008. Non-paraneoplastic limbic encephalitis associated with anti-glutamic acid decarboxylase antibodies. J. Neuroimmunol. 199, 155—159. Nohria, V., Lee, N., Tien, R.D., Heinz, E.R., Smith, J.S., DeLong, G.R., Skeen, M.B., Resnick, T.J., Crain, B., Lewis, D.V., 1994. Magnetic resonance imaging evidence of hippocampal sclerosis in progression: a case report. Epilepsia 35, 1332—1336. Theodore, W.H., Epstein, L., Gaillard, W.D., Shinnar, S., Wainwright, M.S., Jacobson, S., 2008. Human herpes virus 6B: a possible role in epilepsy? Epilepsia 49, 1828—1837. Urbach, H., Soeder, B.M., Jeub, M., Klockgether, T., Meyer, B., Bien, C.G., 2006. Serial MRI of limbic encephalitis. Neuroradiology 48, 380—386. Tien, R.D., Felsberg, G.J., 1995. The hippocampus in status epilepticus: demonstration of signal intensity and morphologic changes with sequential fast spin-echo MR imaging. Radiology 194, 249—256. Van Baalen, A., Häusler, M., Boor, R., Rohr, A., Sperner, J., Kurlemann, G., Panzer, A., Stephani, U., Kluger, G., 2010. Febrile infection-related epilepsy syndrome (FIRES): a nonencephalitic encephalopathy in childhood. Epilepsia (Epub ahead of print). Wieshmann, U.C., Woermann, F.G., Lemieux, L., Free, S.L., Bartlett, P.A., Smith, S.J.M., Duncan, J.S., Stevens, J.M., Shorvon, S.D., 1997. Development of hippocampal atrophy: a serial magnetic resonance imaging study in a patient who developed epilepsy after generalized status epilepticus. Epilepsia 38, 1238—1241.
