FULL-LENGTH ORIGINAL RESEARCH
Early and chronic gray matter volume changes in limbic encephalitis revealed by voxel-based morphometry *†Jan Wagner, *†‡Bernd Weber, and *†‡Christian E. Elger Epilepsia, 56(5):754–761, 2015 doi: 10.1111/epi.12968
SUMMARY
Dr. Jan Wagner is resident, with special interest in imaging, at the Department of Epileptology at the University of Bonn.
Objective: Antibody-associated limbic encephalitis (LE) is an increasingly recognized cause of mostly adult-onset temporal lobe epilepsy. Magnetic resonance imaging (MRI) typically shows volume and signal changes of the mesiotemporal structures. However, recent studies indicate that imaging characteristics depend on the type of the associated antibody. The aim of the present study was to investigate early and chronic gray matter (GM) volume changes in LE by means of voxel-based morphometry (VBM). Methods: Optimized VBM analysis was applied to altogether 73 MRI volumes of 55 patients with antibody-associated LE. Based on the time point of MRI acquisition, patients were split into two separate groups to enable the evaluation of early (≤2 years after LE onset) and chronic (>2 years after LE onset) GM volume changes. In addition, separate analyses for the two most common LE subtypes in our study cohort, that is, glutamic acid decarboxylase (GAD)–associated LE and voltage-gated potassium channel (VGKC)-complex–associated LE were performed. Age- and gender-matched healthy subjects served as controls. Results: Referring to the entire LE group, VBM revealed bi-amygdalar GM volume increase in the early disease stage. In the chronic disease stage, amygdala enlargement had resolved and we found GM volume reduction in the right cerebellar hemisphere. In the subgroup analysis, VBM showed corresponding bi-amygdalar GM volume increase in VGKC-complex–associated LE on early MRI, whereas no changes were found in GAD-associated LE. In the chronic disease stage, VBM revealed left frontal GM volume increase in VGKC-complex–associated LE and right frontoparietal GM volume reduction in GAD-associated LE. Significance: The present study provides further evidence of a predominant affection of the amygdala in the early disease stage of LE, which resolves during the later course of the disease. Furthermore, our results show that LE features distinct imaging characteristics depending on the associated antibody and thus may contribute to a better pathophysiologic understanding of this disease. KEY WORDS: Epilepsy, Magnetic resonance imaging, Voxel-based morphometry, Glutamic acid decarboxylase, Voltage-gated potassium channel-complex, Onconeural.
Accepted February 11, 2015; Early View publication March 23, 2015. *Department of Epileptology, University of Bonn, Bonn, Germany; †Department of NeuroCognition/Imaging, Life & Brain Center, Bonn, Germany; and ‡Center for Economics and Neuroscience, University of Bonn, Bonn, Germany Address correspondence to Jan Wagner, Department of Epileptology, University of Bonn, Sigmund-Freud-Str. 25, D-53127 Bonn, Germany. E-mail: [email protected] Wiley Periodicals, Inc. © 2015 International League Against Epilepsy
Antibody-associated limbic encephalitis (LE) has come up over the past years as an underlying cause of formerly mostly cryptogenic temporal lobe epilepsy.1 Increasingly more autoantibodies are found to be associated with this disorder,2,3 which was described initially as a paraneoplastic syndrome caused by inflammation in limbic structures in adults.4,5 While prognosis in paraneoplastic LE depends mainly on the underlying tumor, clinical outcome in nonparaneoplastic LE seems to be crucially influenced by
754
755 VBM in Limbic Encephalitis the associated antibody. Here, LE associated with antibodies against glutamic acid decarboxylase (GAD) usually shows a nonremitting chronic disease course with seizure and antibody persistence and poor responses to immunotherapy, whereas patients who have LE associated with voltage-gated potassium channel (VGKC)-complex antibodies mostly become seizure-free and antibody-negative during follow-up.3,6–8 Typical features of LE on magnetic resonance imaging (MRI) comprise volume and signal changes of the mesiotemporal structures, which have been demonstrated by both conventional9,10 and postprocessing imaging studies.11 In two recently published studies, we could show that the amygdala seems to be primarily affected by the inflammatory process based on automated MRI signal12 and volumetric analyses.6 Furthermore, in the latter study, we could show that distinct volumetric courses of amygdala and hippocampus in the acute disease stage of GAD-associated LE (GAD-LE) and VGKC-complex–associated LE (VGKCLE) corresponded to distinct clinical and paraclinical features in these two LE subforms. Based on the results of these two studies, the aim of the present study was to evaluate gray matter (GM) volume changes in antibody-associated LE by means of voxel-based morphometry (VBM). We chose VBM, as this is a well-established fully automated processing technique facilitating the detection of GM volume changes in the entire brain, whereas our previous studies were focused mainly on abnormalities of the mesiotemporal structures. The feasibility of VBM in temporal lobe epilepsy has been proven in various studies on hippocampal sclerosis by showing widespread volume reductions even remote from the seizure focus.13 To the best of our knowledge, no studies have applied this technique to LE until now. Because we were particularly interested in early and chronic GM volume changes, two separate study groups were established, depending on the time point of their MRI acquisition. In addition, we performed separate analyses for the two most common LE subtypes in our study cohort, that is, GAD-LE and VGKC-LE.
Methods Study groups We retrospectively evaluated all patients diagnosed with antibody-associated LE presenting at the University of Bonn Department of Epileptology, from April 2006 to August 2013. Patients were diagnosed with LE based on the features of a subacute “limbic” syndrome manifesting in adolescence or adulthood (at least one of the following symptoms: seizures of temporal semiology, disturbance of episodic memory, psychiatric symptoms with affective and/ or anxiety disturbances), and positive serologic antibody results (i.e., onconeural, VGKC-complex, GAD). The patient groups in this study were based on the study cohort from our previous report.6 However, as our previous
work focused mainly on the early disease stage, we additionally aimed at investigating chronic changes in GM volume in the present study. Therefore, the following two separate patient groups were established, depending on the time point of their MRI acquisition: (1) the “early” group, consisting of the earliest available MRI of each included patient acquired not later than 2 years after disease onset (in the following referred to as MRI 1); and (2) the “late” group, consisting of the most recent available MRI performed at least 2 years after disease onset (in the following referred to as MRI 2). Hence, patients who were scanned repeatedly could be included in both MRI 1 and MRI 2 groups if their earliest MRI was performed within the first 2 years after onset and if their most recent MRI was acquired at least 2 years after onset. LE onset was defined as the time point of the first symptoms suggestive of LE (seizures and/or psychiatric and/or mnestic disturbances). As mentioned earlier, these selection criteria were chosen to evaluate early and chronic changes in GM volume and were based on experiences from our previous study,6 which focused mainly on the first 2 years after LE onset. Furthermore, the cutoff value of 2 years enabled similar MRI 1 and MRI 2 group sizes. To achieve the best possible age-matching and gendermatching with the patient groups, two separate control groups consisting of healthy subjects with no neurologic or psychiatric disorder were assembled. These controls were recruited from a preexisting in-house database consisting of 1,342 healthy subjects. Age-matching and gender-matching was achieved by building matched pairs for each individual patient. Informed consent was obtained from all study participants and the study was approved by the ethics committee of the University of Bonn. Antibody tests All patients underwent extensive serum antibody testing. Identification of GAD antibodies in serum was performed by radioimmunoprecipitation assay using 125IGAD (normal values ≤1 U/ml; Weatherall Institute, Oxford, United Kingdom, or EUROIMMUN, L€ubeck, Germany).8 Serum antibodies against the VGKC-complex were assessed by radioimmunoprecipitation assay (normal values
Early and chronic gray matter volume changes in limbic encephalitis revealed by voxel-based morphometry *†Jan Wagner, *†‡Bernd Weber, and *†‡Christian E. Elger Epilepsia, 56(5):754–761, 2015 doi: 10.1111/epi.12968
SUMMARY
Dr. Jan Wagner is resident, with special interest in imaging, at the Department of Epileptology at the University of Bonn.
Objective: Antibody-associated limbic encephalitis (LE) is an increasingly recognized cause of mostly adult-onset temporal lobe epilepsy. Magnetic resonance imaging (MRI) typically shows volume and signal changes of the mesiotemporal structures. However, recent studies indicate that imaging characteristics depend on the type of the associated antibody. The aim of the present study was to investigate early and chronic gray matter (GM) volume changes in LE by means of voxel-based morphometry (VBM). Methods: Optimized VBM analysis was applied to altogether 73 MRI volumes of 55 patients with antibody-associated LE. Based on the time point of MRI acquisition, patients were split into two separate groups to enable the evaluation of early (≤2 years after LE onset) and chronic (>2 years after LE onset) GM volume changes. In addition, separate analyses for the two most common LE subtypes in our study cohort, that is, glutamic acid decarboxylase (GAD)–associated LE and voltage-gated potassium channel (VGKC)-complex–associated LE were performed. Age- and gender-matched healthy subjects served as controls. Results: Referring to the entire LE group, VBM revealed bi-amygdalar GM volume increase in the early disease stage. In the chronic disease stage, amygdala enlargement had resolved and we found GM volume reduction in the right cerebellar hemisphere. In the subgroup analysis, VBM showed corresponding bi-amygdalar GM volume increase in VGKC-complex–associated LE on early MRI, whereas no changes were found in GAD-associated LE. In the chronic disease stage, VBM revealed left frontal GM volume increase in VGKC-complex–associated LE and right frontoparietal GM volume reduction in GAD-associated LE. Significance: The present study provides further evidence of a predominant affection of the amygdala in the early disease stage of LE, which resolves during the later course of the disease. Furthermore, our results show that LE features distinct imaging characteristics depending on the associated antibody and thus may contribute to a better pathophysiologic understanding of this disease. KEY WORDS: Epilepsy, Magnetic resonance imaging, Voxel-based morphometry, Glutamic acid decarboxylase, Voltage-gated potassium channel-complex, Onconeural.
Accepted February 11, 2015; Early View publication March 23, 2015. *Department of Epileptology, University of Bonn, Bonn, Germany; †Department of NeuroCognition/Imaging, Life & Brain Center, Bonn, Germany; and ‡Center for Economics and Neuroscience, University of Bonn, Bonn, Germany Address correspondence to Jan Wagner, Department of Epileptology, University of Bonn, Sigmund-Freud-Str. 25, D-53127 Bonn, Germany. E-mail: [email protected] Wiley Periodicals, Inc. © 2015 International League Against Epilepsy
Antibody-associated limbic encephalitis (LE) has come up over the past years as an underlying cause of formerly mostly cryptogenic temporal lobe epilepsy.1 Increasingly more autoantibodies are found to be associated with this disorder,2,3 which was described initially as a paraneoplastic syndrome caused by inflammation in limbic structures in adults.4,5 While prognosis in paraneoplastic LE depends mainly on the underlying tumor, clinical outcome in nonparaneoplastic LE seems to be crucially influenced by
754
755 VBM in Limbic Encephalitis the associated antibody. Here, LE associated with antibodies against glutamic acid decarboxylase (GAD) usually shows a nonremitting chronic disease course with seizure and antibody persistence and poor responses to immunotherapy, whereas patients who have LE associated with voltage-gated potassium channel (VGKC)-complex antibodies mostly become seizure-free and antibody-negative during follow-up.3,6–8 Typical features of LE on magnetic resonance imaging (MRI) comprise volume and signal changes of the mesiotemporal structures, which have been demonstrated by both conventional9,10 and postprocessing imaging studies.11 In two recently published studies, we could show that the amygdala seems to be primarily affected by the inflammatory process based on automated MRI signal12 and volumetric analyses.6 Furthermore, in the latter study, we could show that distinct volumetric courses of amygdala and hippocampus in the acute disease stage of GAD-associated LE (GAD-LE) and VGKC-complex–associated LE (VGKCLE) corresponded to distinct clinical and paraclinical features in these two LE subforms. Based on the results of these two studies, the aim of the present study was to evaluate gray matter (GM) volume changes in antibody-associated LE by means of voxel-based morphometry (VBM). We chose VBM, as this is a well-established fully automated processing technique facilitating the detection of GM volume changes in the entire brain, whereas our previous studies were focused mainly on abnormalities of the mesiotemporal structures. The feasibility of VBM in temporal lobe epilepsy has been proven in various studies on hippocampal sclerosis by showing widespread volume reductions even remote from the seizure focus.13 To the best of our knowledge, no studies have applied this technique to LE until now. Because we were particularly interested in early and chronic GM volume changes, two separate study groups were established, depending on the time point of their MRI acquisition. In addition, we performed separate analyses for the two most common LE subtypes in our study cohort, that is, GAD-LE and VGKC-LE.
Methods Study groups We retrospectively evaluated all patients diagnosed with antibody-associated LE presenting at the University of Bonn Department of Epileptology, from April 2006 to August 2013. Patients were diagnosed with LE based on the features of a subacute “limbic” syndrome manifesting in adolescence or adulthood (at least one of the following symptoms: seizures of temporal semiology, disturbance of episodic memory, psychiatric symptoms with affective and/ or anxiety disturbances), and positive serologic antibody results (i.e., onconeural, VGKC-complex, GAD). The patient groups in this study were based on the study cohort from our previous report.6 However, as our previous
work focused mainly on the early disease stage, we additionally aimed at investigating chronic changes in GM volume in the present study. Therefore, the following two separate patient groups were established, depending on the time point of their MRI acquisition: (1) the “early” group, consisting of the earliest available MRI of each included patient acquired not later than 2 years after disease onset (in the following referred to as MRI 1); and (2) the “late” group, consisting of the most recent available MRI performed at least 2 years after disease onset (in the following referred to as MRI 2). Hence, patients who were scanned repeatedly could be included in both MRI 1 and MRI 2 groups if their earliest MRI was performed within the first 2 years after onset and if their most recent MRI was acquired at least 2 years after onset. LE onset was defined as the time point of the first symptoms suggestive of LE (seizures and/or psychiatric and/or mnestic disturbances). As mentioned earlier, these selection criteria were chosen to evaluate early and chronic changes in GM volume and were based on experiences from our previous study,6 which focused mainly on the first 2 years after LE onset. Furthermore, the cutoff value of 2 years enabled similar MRI 1 and MRI 2 group sizes. To achieve the best possible age-matching and gendermatching with the patient groups, two separate control groups consisting of healthy subjects with no neurologic or psychiatric disorder were assembled. These controls were recruited from a preexisting in-house database consisting of 1,342 healthy subjects. Age-matching and gender-matching was achieved by building matched pairs for each individual patient. Informed consent was obtained from all study participants and the study was approved by the ethics committee of the University of Bonn. Antibody tests All patients underwent extensive serum antibody testing. Identification of GAD antibodies in serum was performed by radioimmunoprecipitation assay using 125IGAD (normal values ≤1 U/ml; Weatherall Institute, Oxford, United Kingdom, or EUROIMMUN, L€ubeck, Germany).8 Serum antibodies against the VGKC-complex were assessed by radioimmunoprecipitation assay (normal values
