Journal of Neuroimmunology 271 (2014) 53–55
Contents lists available at ScienceDirect
Journal of Neuroimmunology journal homepage: www.elsevier.com/locate/jneuroim
Short communication
Serial brain 18FDG-PET in anti-AMPA receptor limbic encephalitis Marianna Spatola a, Vesna Stojanova a, John O. Prior b, Josep Dalmau c,d, Andrea O. Rossetti a,⁎ a
Service of Neurology, Department of Clinical Neuroscience, CHUV and University of Lausanne, Lausanne, Switzerland Department of Nuclear Medicine, CHUV and University of Lausanne, Lausanne, Switzerland c IDIBAPS and Service of Neurology, Hospital Clinic, University of Barcelona, Barcelona, Spain d Department of Neurology, University of Pennsylvania, Philadelphia, United States b
a r t i c l e
i n f o
Article history: Received 2 January 2014 Received in revised form 5 March 2014 Accepted 8 April 2014
Keywords: Biomarker Disease activity Complementary exam Follow-up Therapy 18 FDG PET
a b s t r a c t Immunotherapy-responsive autoimmune CNS syndromes linked to antibodies targeting surface neuronal antigens lack reliable biomarkers of disease activity. We report serial cerebral 18FDG PET studies in a woman with AMPA receptor (AMPA-R) autoimmune limbic encephalitis. During her follow-up, despite an aggressive immunotherapy, she displayed a persistent, predominantly left hippocampal FDG hypermetabolism, in the absence of CNS inflammatory signs. Brain metabolism abnormalities regressed after increasing antiepileptic treatment, correlating with a moderate clinical improvement. Brain 18F-FDG PET could thus represent a useful complementary tool to orient the clinical follow-up. © 2014 Elsevier B.V. All rights reserved.
1. Introduction The recent discovery of autoantibodies against neuronal surface antigens has allowed refining the knowledge about autoimmune encephalitis, including limbic encephalitis (LE), and has contributed to change the prognosis, given the immunotherapy responsiveness, unlike paraneoplastic LE. As opposed to other autoimmune forms, such as those induced by NMDA-receptor or LGI1 autoantibodies (Irani et al., 2013), AMPA receptor (AMPA-R) encephalitis is rarely observed, and its clinical course is not well known. In this setting, sorting out the relative role of inflammation and seizures in the pathogenesis of the symptoms has an obvious impact on therapeutic decisions, but can represent a daunting task. We performed a 35-month follow-up based on serial EEG, MRI, and glucose brain metabolism (18FDG PET) to investigate disease activity in one of our patients. 2. Case description In June 2010, a previously healthy 33-year-old woman presented a first generalized seizure and received levetiracetam in an outside clinic, because of brain MRI abnormalities. At that time she also experienced up to 10 daily episodes of brief gastric discomfort and olfactory hallucinations. One month later, she was referred to our hospital because of ⁎ Corresponding author at: CHUV-BH07, CH-1011 Lausanne, Switzerland. E-mail address: [email protected] (A.O. Rossetti).
http://dx.doi.org/10.1016/j.jneuroim.2014.04.002 0165-5728/© 2014 Elsevier B.V. All rights reserved.
progressive memory problems. While her physical and neurological status was unrevealing, neuropsychological tests outlined a profound, isolated episodic anterograde global memory loss, associated with semantic and autobiographic retrograde memory deficits. Her EEG showed a theta slowing in the bi-temporal regions with periodic lateralized epileptiform discharges (PLEDs) of shifting lateralization; brain MRI revealed T2 and FLAIR hyperintensities initially confined to the left hippocampus, but eventually becoming bilateral; extended blood tests were normal; a slight pleocytosis (9 white blood cell/mm3) with normal protein and glucose concentrations were found in the CSF analysis, without oligoclonal bands, and a negative infection work-up. Determination of antibodies using both immunohistochemistry with rat brain and cell-based assays, as previously described (Lai et al., 2009), demonstrated AMPA-R antibodies in serum and CSF, confirming the clinical diagnosis of autoimmune LE. Oncologic screening remained negative over the following 3 years. Generalized seizures were rapidly controlled with antiepileptic drugs (levetiracetam changed to pregabalin because of irritability), and the patient underwent a 15-month immunotherapy, combining intravenous methylprednisolone 1000 mg/day for 5 days, relayed by oral prednisone at decreasing doses over 15 months, 8 plasma exchanges (once a week), followed by 5 cycles of intravenous cyclophosphamide (1500 mg/month) and 4 perfusions of rituximab (375 mg/m2 once a week), as illustrated in Fig. 1a. Follow-up was performed through clinical and neuropsychological evaluations, CSF and serum antibody assessments, serial cerebral MRI, EEG, and brain 18FDG PET scans (Fig. 1a, b).
54
M. Spatola et al. / Journal of Neuroimmunology 271 (2014) 53–55
Fig. 1. (a) Disease evolution over 35 months (horizontal axis corresponds to months after disease onset). First graphic shows immunotherapy (CS = corticosteroids; PE = plasma exchanges; CPA = Cyclophosphamide; RTX = Rituximab) and antiepileptic drugs (LEV = levetiracetam; PGB = pregabalin, LTG = lamotrigine, ZNS = zonisamide). Second graphic shows decrease of CSF pleocytosis together with CSF and serum antibody levels over time (Ab = antibody; WBC = white blood cells; vertical axis shows antibody titres in a logarithmic scale (100 = dilution 1:100) and white blood cells/mm3). Third graphic shows changes of follow-up examinations (18-FDG PET, MRI, EEG and neuropsychological evaluation) over time (L = left; R = right; H = hippocampal; M = metabolism; I = intensity; Bi = bilateral; T = temporal; PLEDs = periodic lateralized epileptiform discharges; Npsy: neuropsychological test; Imp = impossible; Poss = possible; DR = delayed recall at 10 or 15 words learning test). (b–d) Evolution of 18FDG PET over time showing left more than right hippocampal hypermetabolism 3 months after disease onset (b), which significantly regressed at 10 months (c) and almost disappeared at 25 months (d) after disease onset.
Evolution was characterized by the persistence of a severe amnesic syndrome, with important functional impact, but better management of everyday life activities thanks to various devices and copying strategies (such as an electronic agenda with multiple alarms). As shown in Fig. 1a, inflammatory parameters improved rapidly, and (Fig. 2) MRI hippocampal edema decreased, evolving into focal atrophy. In contrast, surface EEG demonstrated persistent bilateral temporal, monotonous PLEDs, essentially during sleep and drowsiness, correlating with predominantly left hippocampal glucose hypermetabolism and rare olfactory seizures. Hypothesizing that lack of clinical changes after 15-month immunotherapy might have been related to ongoing temporal seizures rather than brain inflammation, we potentiated the antiepileptic therapy (first with a progressive increase of pregabalin, which was not well tolerated, then by adding lamotrigine, and finally switching between pregabalin and high dose zonisamide). A notable memory improvement over the following 3 months was observed, reflected by better scores at the Kopelmann test, concerning semantic and episodic memory, and better learning, recognition and delayed recall at the 10 or 15 words test. In February 2014, at last follow-up visit, the patient was stable; PET metabolic abnormalities had finally resolved in June 2013 (Fig. 1b), although electric epileptiform activity remained globally unchanged. 3. Discussion This young woman who developed non-paraneoplastic LE linked to AMPA-R autoantibodies, experienced clinical stabilization with immunotherapy and antiepileptic drugs. She was followed-up with serial brain 18FDG PET imaging showing persistent hypermetabolic hippocampal foci, correlating with ongoing epileptic activity on EEG, but not CSF inflammation, and experienced clinical improvement after potentiating antiepileptic treatment, with brain glucose metabolism normalization. AMPA-R mediates cerebral fast excitatory glutamate transmission and has been recently recognized to be an antigenic target for CNS autoantibodies (Lai et al., 2009). All AMPA-R encephalitis patients reported in literature (less than 20 cases described so far) are women with
Fig. 2. Serial brain MRI at 3 (a), 4 (b), 9 (c), 13 (d), 17 (e) and 35 (f) months after disease onset showing bilateral (left more than right) T2 hyperintensities in hippocampi, progressively replaced by hippocampal atrophy (mostly right) (e,f).
M. Spatola et al. / Journal of Neuroimmunology 271 (2014) 53–55
symptoms similar to our patient, and identification of a tumor (breast, lung or thymus) in the majority of cases (70%) (Lancaster et al., 2011); mesio-temporal lobe hyperintensities and edema in brain MRI are characteristic. Progression to hippocampal atrophy, as experienced by our patient, has been described in paraneoplastic (Urbach et al., 2006),(Ances et al., 2005) and non-paraneoplastic LE (Kröll-Seger et al., 2009), (Sharma et al., 2012), but to the best of our knowledge it has never been reported in AMPA-R encephalitis. Even if seizures represent a common clinical feature, interictal EEG often fails to demonstrate epileptic activity, likely because of the mesiotemporal location (Lai et al., 2009). Response to immunotherapy is generally excellent, with complete recovery in most, but not all subjects, and partial response after relapses (Lai et al., 2009). To date, no precise treatment guidelines are available, and the clinical approach is generally translated from the experience on other more frequent autoimmune encephalitis, particularly those linked to NMDA-R (Lai et al., 2009; Titulaer et al., 2013). In this context, it seems important to identify reliable biomarkers, which can reflect disease activity and predict response to treatment. Brain 18FDG PET has been demonstrated to be useful in the diagnostic work-up of infectious/inflammatory encephalitis (Lee et al., 2004). Previous studies (Ances et al., 2005) on LE (but not AMPA-R) have described variable hypermetabolism in limbic structures, sometimes associated with hypermetabolic cerebellum, brainstem and insula. Nevertheless, its role in monitoring disease activity has not been thoroughly explored. In our patient, cerebral PET showed persisting hypermetabolism in the hippocampi, strongly predominating on the left (Fig. 1b–d), raising the important question whether hyperactivity was due to inflammation or ongoing seizures. The first hypothesis seemed unlikely, since all inflammatory parameters (CSF pleocytosis, antibody level and MRI hyperintensities) had rapidly decreased following immunological suppression. The second assumption, in contrast, appeared probable, in presence of persistent electric epileptic activity on the EEG and ongoing focal seizures, and was supported by the observation of clinical improvement after potentiating antiepileptic therapy, with normalization of brain glucose metabolism, disappearance of focal seizures, and memory improvement. The lack of significant improvement of the EEG abnormalities over time might correspond to a sort of epileptic “scar” at one end of the ictal–interictal continuum (Chong and Hirsch, 2005), rather than reflecting active epileptic activity; in fact, the PLEDs remained mostly monotonous at the end of the follow-up (24 h EEG monitoring), without any sign of epileptic seizure. Our observation is of potential clinical relevance, since cerebral PET imaging could represent an important, non-invasive additional tool for
55
disease activity monitoring, especially when inflammatory parameters seem to be controlled under an immune-modulatory therapy, and could orientate follow-up management and therapeutic decisions. Further studies are needed to confirm our findings and widen our understanding of the role of inflammation and seizures in determining neuropsychological disturbances in patients with LE.
Acknowledgments Prof R. Du Pasquier, Prof J.-F. Demonet, Mrs. V. Beaud, Dipl. Psych., Department of Clinical Neuroscience, CHUV and University of Lausanne, Switzerland, and Dr T. Bill and Mrs. F. Colombo, Dipl. Psych., Hospital of Fribourg, Switzerland, contributed to the clinical follow-up of this patient.
References Ances, B.M., Vitaliani, R., Taylor, R.A., Liebeskind, D.S., Voloschin, A., Houghton, D.J., Galetta, S.L., Dichter, M., Alavi, A., Rosenfeld, M.R., Dalmau, J., 2005. Treatmentresponsive limbic encephalitis identified by neuropil antibodies: MRI and PET correlates. Brain 128, 1764–1777. Chong, D.J., Hirsch, L.J., 2005. Which EEG patterns warrant treatment in the critically ill? Reviewing the evidence for treatment of periodic epileptiform discharges and related patterns. J. Clin. Neurophysiol. 22, 79–91. Irani, S.R., Stagg, C.J., Schott, J.M., Rosenthal, C.R., Schneider, S.A., Pettingill, P., Pettingill, R., Waters, P., Thomas, A., Voets, N.L., Cardoso, M.J., Cash, D.M., Manning, E.N., Lang, B., Smith, S.J., Vincent, A., Johnson, M.R., 2013. Faciobrachial dystonic seizures: the influence of immunotherapy on seizure control and prevention of cognitive impairment in a broadening phenotype. Brain 136, 3151–3162. Kröll-Seger, J., Bien, C.G., Huppertz, H.J., 2009. Non-paraneoplastic limbic encephalitis associated with antibodies to potassium channels leading to bilateral hippocampal sclerosis in a pre-pubertal girl. Epileptic Disord. 11, 54–59. Lai, M., Hughes, E.G., Peng, X., Zhou, L., Gleichman, A.J., Shu, H., Matà, S., Kremens, D., Vitaliani, R., Geschwind, M.D., Bataller, L., Kalb, R.G., Davis, R., Graus, F., Lynch, D.R., Balice-Gordon, R., Dalmau, J., 2009. AMPA receptor antibodies in limbic encephalitis alter synaptic receptor location. Ann. Neurol. 65, 424–434. Lancaster, E., Martinez-Hernandez, E., Dalmau, J., 2011. Encephalitis and antibodies to synaptic and neuronal cell surface proteins. Neurology 77, 179–189. Lee, B.Y., Newberg, A.B., Liebeskind, D.S., Kung, J., Alavi, A., 2004. FDG-PET findings in patients with suspected encephalitis. Clin. Nucl. Med. 29, 620–625. Sharma, A., Dubey, D., Sawhney, A., Janga, K., 2012. GAD65 positive autoimmune limbic encephalitis: a case report and review of literature. J. Clin. Med. Res. 4, 424–428. Titulaer, M.J., McCracken, L., Gabilondo, I., Armangué, T., Glaser, C., Iizuka, T., Honig, L.S., Benseler, S.M., Kawachi, I., Martinez-Hernandez, E., Aguilar, E., Gresa-Arribas, N., Ryan-Florance, N., Torrents, A., Saiz, A., Rosenfeld, M.R., Balice-Gordon, R., Graus, F., Dalmau, J., 2013. Treatment and prognostic factors for long-term outcome in patients with anti-NMDA receptor encephalitis: an observational cohort study. Lancet Neurol. 12, 157–165. Urbach, H., Soeder, B.M., Jeub, M., Klockgether, T., Meyer, B., Bien, C.G., 2006. Serial MRI of limbic encephalitis. Neuroradiology 48, 380–386.
Contents lists available at ScienceDirect
Journal of Neuroimmunology journal homepage: www.elsevier.com/locate/jneuroim
Short communication
Serial brain 18FDG-PET in anti-AMPA receptor limbic encephalitis Marianna Spatola a, Vesna Stojanova a, John O. Prior b, Josep Dalmau c,d, Andrea O. Rossetti a,⁎ a
Service of Neurology, Department of Clinical Neuroscience, CHUV and University of Lausanne, Lausanne, Switzerland Department of Nuclear Medicine, CHUV and University of Lausanne, Lausanne, Switzerland c IDIBAPS and Service of Neurology, Hospital Clinic, University of Barcelona, Barcelona, Spain d Department of Neurology, University of Pennsylvania, Philadelphia, United States b
a r t i c l e
i n f o
Article history: Received 2 January 2014 Received in revised form 5 March 2014 Accepted 8 April 2014
Keywords: Biomarker Disease activity Complementary exam Follow-up Therapy 18 FDG PET
a b s t r a c t Immunotherapy-responsive autoimmune CNS syndromes linked to antibodies targeting surface neuronal antigens lack reliable biomarkers of disease activity. We report serial cerebral 18FDG PET studies in a woman with AMPA receptor (AMPA-R) autoimmune limbic encephalitis. During her follow-up, despite an aggressive immunotherapy, she displayed a persistent, predominantly left hippocampal FDG hypermetabolism, in the absence of CNS inflammatory signs. Brain metabolism abnormalities regressed after increasing antiepileptic treatment, correlating with a moderate clinical improvement. Brain 18F-FDG PET could thus represent a useful complementary tool to orient the clinical follow-up. © 2014 Elsevier B.V. All rights reserved.
1. Introduction The recent discovery of autoantibodies against neuronal surface antigens has allowed refining the knowledge about autoimmune encephalitis, including limbic encephalitis (LE), and has contributed to change the prognosis, given the immunotherapy responsiveness, unlike paraneoplastic LE. As opposed to other autoimmune forms, such as those induced by NMDA-receptor or LGI1 autoantibodies (Irani et al., 2013), AMPA receptor (AMPA-R) encephalitis is rarely observed, and its clinical course is not well known. In this setting, sorting out the relative role of inflammation and seizures in the pathogenesis of the symptoms has an obvious impact on therapeutic decisions, but can represent a daunting task. We performed a 35-month follow-up based on serial EEG, MRI, and glucose brain metabolism (18FDG PET) to investigate disease activity in one of our patients. 2. Case description In June 2010, a previously healthy 33-year-old woman presented a first generalized seizure and received levetiracetam in an outside clinic, because of brain MRI abnormalities. At that time she also experienced up to 10 daily episodes of brief gastric discomfort and olfactory hallucinations. One month later, she was referred to our hospital because of ⁎ Corresponding author at: CHUV-BH07, CH-1011 Lausanne, Switzerland. E-mail address: [email protected] (A.O. Rossetti).
http://dx.doi.org/10.1016/j.jneuroim.2014.04.002 0165-5728/© 2014 Elsevier B.V. All rights reserved.
progressive memory problems. While her physical and neurological status was unrevealing, neuropsychological tests outlined a profound, isolated episodic anterograde global memory loss, associated with semantic and autobiographic retrograde memory deficits. Her EEG showed a theta slowing in the bi-temporal regions with periodic lateralized epileptiform discharges (PLEDs) of shifting lateralization; brain MRI revealed T2 and FLAIR hyperintensities initially confined to the left hippocampus, but eventually becoming bilateral; extended blood tests were normal; a slight pleocytosis (9 white blood cell/mm3) with normal protein and glucose concentrations were found in the CSF analysis, without oligoclonal bands, and a negative infection work-up. Determination of antibodies using both immunohistochemistry with rat brain and cell-based assays, as previously described (Lai et al., 2009), demonstrated AMPA-R antibodies in serum and CSF, confirming the clinical diagnosis of autoimmune LE. Oncologic screening remained negative over the following 3 years. Generalized seizures were rapidly controlled with antiepileptic drugs (levetiracetam changed to pregabalin because of irritability), and the patient underwent a 15-month immunotherapy, combining intravenous methylprednisolone 1000 mg/day for 5 days, relayed by oral prednisone at decreasing doses over 15 months, 8 plasma exchanges (once a week), followed by 5 cycles of intravenous cyclophosphamide (1500 mg/month) and 4 perfusions of rituximab (375 mg/m2 once a week), as illustrated in Fig. 1a. Follow-up was performed through clinical and neuropsychological evaluations, CSF and serum antibody assessments, serial cerebral MRI, EEG, and brain 18FDG PET scans (Fig. 1a, b).
54
M. Spatola et al. / Journal of Neuroimmunology 271 (2014) 53–55
Fig. 1. (a) Disease evolution over 35 months (horizontal axis corresponds to months after disease onset). First graphic shows immunotherapy (CS = corticosteroids; PE = plasma exchanges; CPA = Cyclophosphamide; RTX = Rituximab) and antiepileptic drugs (LEV = levetiracetam; PGB = pregabalin, LTG = lamotrigine, ZNS = zonisamide). Second graphic shows decrease of CSF pleocytosis together with CSF and serum antibody levels over time (Ab = antibody; WBC = white blood cells; vertical axis shows antibody titres in a logarithmic scale (100 = dilution 1:100) and white blood cells/mm3). Third graphic shows changes of follow-up examinations (18-FDG PET, MRI, EEG and neuropsychological evaluation) over time (L = left; R = right; H = hippocampal; M = metabolism; I = intensity; Bi = bilateral; T = temporal; PLEDs = periodic lateralized epileptiform discharges; Npsy: neuropsychological test; Imp = impossible; Poss = possible; DR = delayed recall at 10 or 15 words learning test). (b–d) Evolution of 18FDG PET over time showing left more than right hippocampal hypermetabolism 3 months after disease onset (b), which significantly regressed at 10 months (c) and almost disappeared at 25 months (d) after disease onset.
Evolution was characterized by the persistence of a severe amnesic syndrome, with important functional impact, but better management of everyday life activities thanks to various devices and copying strategies (such as an electronic agenda with multiple alarms). As shown in Fig. 1a, inflammatory parameters improved rapidly, and (Fig. 2) MRI hippocampal edema decreased, evolving into focal atrophy. In contrast, surface EEG demonstrated persistent bilateral temporal, monotonous PLEDs, essentially during sleep and drowsiness, correlating with predominantly left hippocampal glucose hypermetabolism and rare olfactory seizures. Hypothesizing that lack of clinical changes after 15-month immunotherapy might have been related to ongoing temporal seizures rather than brain inflammation, we potentiated the antiepileptic therapy (first with a progressive increase of pregabalin, which was not well tolerated, then by adding lamotrigine, and finally switching between pregabalin and high dose zonisamide). A notable memory improvement over the following 3 months was observed, reflected by better scores at the Kopelmann test, concerning semantic and episodic memory, and better learning, recognition and delayed recall at the 10 or 15 words test. In February 2014, at last follow-up visit, the patient was stable; PET metabolic abnormalities had finally resolved in June 2013 (Fig. 1b), although electric epileptiform activity remained globally unchanged. 3. Discussion This young woman who developed non-paraneoplastic LE linked to AMPA-R autoantibodies, experienced clinical stabilization with immunotherapy and antiepileptic drugs. She was followed-up with serial brain 18FDG PET imaging showing persistent hypermetabolic hippocampal foci, correlating with ongoing epileptic activity on EEG, but not CSF inflammation, and experienced clinical improvement after potentiating antiepileptic treatment, with brain glucose metabolism normalization. AMPA-R mediates cerebral fast excitatory glutamate transmission and has been recently recognized to be an antigenic target for CNS autoantibodies (Lai et al., 2009). All AMPA-R encephalitis patients reported in literature (less than 20 cases described so far) are women with
Fig. 2. Serial brain MRI at 3 (a), 4 (b), 9 (c), 13 (d), 17 (e) and 35 (f) months after disease onset showing bilateral (left more than right) T2 hyperintensities in hippocampi, progressively replaced by hippocampal atrophy (mostly right) (e,f).
M. Spatola et al. / Journal of Neuroimmunology 271 (2014) 53–55
symptoms similar to our patient, and identification of a tumor (breast, lung or thymus) in the majority of cases (70%) (Lancaster et al., 2011); mesio-temporal lobe hyperintensities and edema in brain MRI are characteristic. Progression to hippocampal atrophy, as experienced by our patient, has been described in paraneoplastic (Urbach et al., 2006),(Ances et al., 2005) and non-paraneoplastic LE (Kröll-Seger et al., 2009), (Sharma et al., 2012), but to the best of our knowledge it has never been reported in AMPA-R encephalitis. Even if seizures represent a common clinical feature, interictal EEG often fails to demonstrate epileptic activity, likely because of the mesiotemporal location (Lai et al., 2009). Response to immunotherapy is generally excellent, with complete recovery in most, but not all subjects, and partial response after relapses (Lai et al., 2009). To date, no precise treatment guidelines are available, and the clinical approach is generally translated from the experience on other more frequent autoimmune encephalitis, particularly those linked to NMDA-R (Lai et al., 2009; Titulaer et al., 2013). In this context, it seems important to identify reliable biomarkers, which can reflect disease activity and predict response to treatment. Brain 18FDG PET has been demonstrated to be useful in the diagnostic work-up of infectious/inflammatory encephalitis (Lee et al., 2004). Previous studies (Ances et al., 2005) on LE (but not AMPA-R) have described variable hypermetabolism in limbic structures, sometimes associated with hypermetabolic cerebellum, brainstem and insula. Nevertheless, its role in monitoring disease activity has not been thoroughly explored. In our patient, cerebral PET showed persisting hypermetabolism in the hippocampi, strongly predominating on the left (Fig. 1b–d), raising the important question whether hyperactivity was due to inflammation or ongoing seizures. The first hypothesis seemed unlikely, since all inflammatory parameters (CSF pleocytosis, antibody level and MRI hyperintensities) had rapidly decreased following immunological suppression. The second assumption, in contrast, appeared probable, in presence of persistent electric epileptic activity on the EEG and ongoing focal seizures, and was supported by the observation of clinical improvement after potentiating antiepileptic therapy, with normalization of brain glucose metabolism, disappearance of focal seizures, and memory improvement. The lack of significant improvement of the EEG abnormalities over time might correspond to a sort of epileptic “scar” at one end of the ictal–interictal continuum (Chong and Hirsch, 2005), rather than reflecting active epileptic activity; in fact, the PLEDs remained mostly monotonous at the end of the follow-up (24 h EEG monitoring), without any sign of epileptic seizure. Our observation is of potential clinical relevance, since cerebral PET imaging could represent an important, non-invasive additional tool for
55
disease activity monitoring, especially when inflammatory parameters seem to be controlled under an immune-modulatory therapy, and could orientate follow-up management and therapeutic decisions. Further studies are needed to confirm our findings and widen our understanding of the role of inflammation and seizures in determining neuropsychological disturbances in patients with LE.
Acknowledgments Prof R. Du Pasquier, Prof J.-F. Demonet, Mrs. V. Beaud, Dipl. Psych., Department of Clinical Neuroscience, CHUV and University of Lausanne, Switzerland, and Dr T. Bill and Mrs. F. Colombo, Dipl. Psych., Hospital of Fribourg, Switzerland, contributed to the clinical follow-up of this patient.
References Ances, B.M., Vitaliani, R., Taylor, R.A., Liebeskind, D.S., Voloschin, A., Houghton, D.J., Galetta, S.L., Dichter, M., Alavi, A., Rosenfeld, M.R., Dalmau, J., 2005. Treatmentresponsive limbic encephalitis identified by neuropil antibodies: MRI and PET correlates. Brain 128, 1764–1777. Chong, D.J., Hirsch, L.J., 2005. Which EEG patterns warrant treatment in the critically ill? Reviewing the evidence for treatment of periodic epileptiform discharges and related patterns. J. Clin. Neurophysiol. 22, 79–91. Irani, S.R., Stagg, C.J., Schott, J.M., Rosenthal, C.R., Schneider, S.A., Pettingill, P., Pettingill, R., Waters, P., Thomas, A., Voets, N.L., Cardoso, M.J., Cash, D.M., Manning, E.N., Lang, B., Smith, S.J., Vincent, A., Johnson, M.R., 2013. Faciobrachial dystonic seizures: the influence of immunotherapy on seizure control and prevention of cognitive impairment in a broadening phenotype. Brain 136, 3151–3162. Kröll-Seger, J., Bien, C.G., Huppertz, H.J., 2009. Non-paraneoplastic limbic encephalitis associated with antibodies to potassium channels leading to bilateral hippocampal sclerosis in a pre-pubertal girl. Epileptic Disord. 11, 54–59. Lai, M., Hughes, E.G., Peng, X., Zhou, L., Gleichman, A.J., Shu, H., Matà, S., Kremens, D., Vitaliani, R., Geschwind, M.D., Bataller, L., Kalb, R.G., Davis, R., Graus, F., Lynch, D.R., Balice-Gordon, R., Dalmau, J., 2009. AMPA receptor antibodies in limbic encephalitis alter synaptic receptor location. Ann. Neurol. 65, 424–434. Lancaster, E., Martinez-Hernandez, E., Dalmau, J., 2011. Encephalitis and antibodies to synaptic and neuronal cell surface proteins. Neurology 77, 179–189. Lee, B.Y., Newberg, A.B., Liebeskind, D.S., Kung, J., Alavi, A., 2004. FDG-PET findings in patients with suspected encephalitis. Clin. Nucl. Med. 29, 620–625. Sharma, A., Dubey, D., Sawhney, A., Janga, K., 2012. GAD65 positive autoimmune limbic encephalitis: a case report and review of literature. J. Clin. Med. Res. 4, 424–428. Titulaer, M.J., McCracken, L., Gabilondo, I., Armangué, T., Glaser, C., Iizuka, T., Honig, L.S., Benseler, S.M., Kawachi, I., Martinez-Hernandez, E., Aguilar, E., Gresa-Arribas, N., Ryan-Florance, N., Torrents, A., Saiz, A., Rosenfeld, M.R., Balice-Gordon, R., Graus, F., Dalmau, J., 2013. Treatment and prognostic factors for long-term outcome in patients with anti-NMDA receptor encephalitis: an observational cohort study. Lancet Neurol. 12, 157–165. Urbach, H., Soeder, B.M., Jeub, M., Klockgether, T., Meyer, B., Bien, C.G., 2006. Serial MRI of limbic encephalitis. Neuroradiology 48, 380–386.
