Downloaded from jnnp.bmj.com on September 4, 2014 - Published by group.bmj.com
JNNP Online First, published on September 2, 2014 as 10.1136/jnnp-2014-307875 Epilepsy
RESEARCH PAPER
Automated volumetry of the mesiotemporal structures in antibody-associated limbic encephalitis Jan Wagner,1,2 Juri-Alexander Witt,1 Christoph Helmstaedter,1 Michael P Malter,1,3 Bernd Weber,1,2,4 Christian E Elger1,2,4 ▸ Additional material is published online only. To view please visit the journal online (http://dx.doi.org/10.1136/ jnnp-2014-307875). 1
Department of Epileptology, University of Bonn, Bonn, Germany 2 Department of NeuroCognition/Imaging, Life & Brain Center, Bonn, Germany 3 Department of Neurology, Marien-Krankenhaus, Bergisch Gladbach, Germany 4 Center for Economics and Neuroscience, University of Bonn, Bonn, Germany Correspondence to Dr Jan Wagner, Department of Epileptology, University of Bonn, Sigmund-Freud-Str. 25, Bonn D-53127, Germany; jan. [email protected] Received 13 February 2014 Revised 31 July 2014 Accepted 12 August 2014
ABSTRACT Objective Limbic encephalitis (LE) is an autoimmune mediated disease leading to temporal lobe epilepsy, mnestic and psychiatric symptoms. In recent years, several LE subforms defined by serum antibody findings have been described. MRI usually shows volume changes of the amygdala and hippocampus. However, studies quantifying longitudinal volume changes in the acute disease stage are lacking. Methods The aim of this retrospective observational study was to evaluate and quantify these volume changes by applying a fully automated volumetric approach to serial MRIs of 28 patients with antibody-associated LE. The results were compared with those of 28 age-matched and gender-matched healthy controls and analysed separately for the different antibody profiles and correlated with clinical parameters. Antibody profile analyses were exploratory due to the relatively small sample sizes. Results We found distinct volumetric and clinical courses depending on the associated antibody. While LE associated with voltage-gated potassium channel-complex antibodies (VGKC-LE) showed highly significant larger volumes of both the amygdala and the hippocampus within the first 12 months after disease onset, LE associated with glutamic acid decarboxylase antibodies (GAD-LE) only displayed greater amygdala volumes at this disease stage. Both subgroups showed a reduction of the amygdala and hippocampus volumes during follow-up with higher volume changes in VGKC-LE. Conclusions These differences in the volumetric evolution corresponded to distinct clinical courses in terms of a more severe initial symptomatology regarding seizure, mnestic and psychiatric disturbances in VGKC-LE, which improved rapidly, corresponding to the evolution of the volumetric changes. In contrast to this, patients with GADLE were less severely affected at disease onset, showing a more unmodulated and chronic disease course during follow-up.
INTRODUCTION
To cite: Wagner J, Witt J-A, Helmstaedter C, et al. J Neurol Neurosurg Psychiatry Published Online First: [please include Day Month Year] doi:10.1136/jnnp2014-307875
Limbic encephalitis (LE) is an autoimmunemediated disease leading to temporal lobe epilepsy, mnestic deficits and psychiatric symptoms.1 2 It was first described in the 1960s as a paraneoplastic syndrome caused by inflammation in limbic structures in adults.3 4 Various onconeural antibodies, which are biomarkers for these paraneoplastic syndromes, have been discovered in the following decades.5 However, in recent years, non-paraneoplastic forms of LE have been increasingly recognised, associated with antibodies against glutamic acid decarboxylase (GAD) and the voltage-gated potassium channel
(VGKC)-complex.6–9 These non-paraneoplastic forms have a better prognosis, but the outcome seems to differ between the two subgroups depending on the associated antibody. While patients with VGKC-complex-associated LE (VGKC-LE) mostly become seizure-free and show normalised antibody concentrations after immunotherapy, GAD-associated LE (GAD-LE) often displays a non-remitting course with antibody and seizure persistence.6 8 10 MRI in LE shows signal and volume changes of the mesiotemporal structures. However, studies quantifying volume changes in LE are scarce. In a recently published study, Irani et al11 found smaller volumes of the whole brain and hippocampus (HC) in VGKC-LE compared to healthy controls. However, MRI was performed in the convalescent phase of the disease and neither amygdala (AM) volumes nor longitudinal volume changes were investigated. The aim of the present study was to evaluate and quantify longitudinal volume changes of AM and HC in the acute and subacute disease stages of antibody-associated LE compared to healthy controls using a fully automated volumetric approach. Furthermore, results were analysed depending on the associated antibody and correlated with clinical parameters (eg, seizure outcome, mnestic and psychiatric symptoms). In doing so, we aimed at addressing the following questions: (1) Is there a difference in AM and HC volumes between patients with LE and healthy participants? (2) How is the temporal evolution of the volumetric changes? (3) Do volumetric changes correlate with clinical parameters? (4) Can we find distinct volumetric and clinical results depending on the associated antibody?
MATERIALS AND METHODS Study groups and MRI examinations We retrospectively studied all patients diagnosed with antibody-associated LE presenting at the Department of Epileptology, University of Bonn, from 1 January 2006 to 31 August 2012. LE was diagnosed based on the features of (1) limbic signs and symptoms, which manifested themselves in adolescence or adulthood (≥one of the following: seizures of temporal semiology, disturbance of episodic memory, psychiatric symptoms with affective and/or anxiety disturbances) and (2) presence of serum antibodies associated with LE (ie, onconeural, VGKC-complex, GAD). Serum antibody testing for GAD, onconeural and VGKC-complex antibodies was performed as described previously.12 Antibodies against leucine-
al. J Neurol Neurosurg 2014;0:1–8. doi:10.1136/jnnp-2014-307875 Copyright Article author (orWagner theirJ, etemployer) 2014.Psychiatry Produced by BMJ Publishing Group Ltd under licence.
1
Downloaded from jnnp.bmj.com on September 4, 2014 - Published by group.bmj.com
Epilepsy rich, glioma inactivated 1 protein (LGI1) and contactin-associated protein-2 (CASPR2) were detected by indirect immunofluorescence using formalin fixed HEK293 cells containing membrane bound LGI1 or CASPR2.13 To allow for an evaluation of the volume changes in the acute disease stage and to assess all included patients at the same disease period, we only included patients whose first MRI including a three-dimensional (3D) T1-weighted volume data set was performed within the first 12 months after LE onset. LE onset was defined as the time point of the first symptoms suggestive of LE (seizures and/or psychiatric and/or mnestic disturbances). If available, we furthermore analysed up to two follow-up MRIs each six to 12 months after the preceding MRI scan to assess the course of the volume changes within the first 36 months of the disease. The control group was assembled from a pre-existing in-house database consisting of 1262 healthy participants with no neurological disorder. Age-matching and gender-matching with the LE group was achieved by building matched pairs for each individual patient. The MRIs of the selected controls were thoroughly inspected and were free of lesions especially in the mesiotemporal region. We did not exclude controls with unspecific extratemporal lesions on MRI (eg, microangiopathy). As follow-up MRI examinations with resembling time intervals were not available for the control group, the control group for the patients’ follow-up MRIs consisted of the corresponding matched participants (ie, for each missing patient, the corresponding matched participant was excluded). All included patients and healthy participants underwent at least one MRI examination including a 3D T1-weighted volume data set using the same 3T MRI scanner (Magnetom Trio, Siemens, Erlangen, Germany) with the same sequence parameters in all participants (MP-RAGE, voxel size 1×1×1 mm, repetition time 1570 ms, echo time 3.42 ms, flip angle 15°, field of view 256 mm×256 mm).
Statistical analysis Statistical analyses were performed using SPSS Statistics V.21.0 for Mac OS X (IBM, Armonk, New York, USA). All values throughout this report are given as median unless otherwise stated. For statistical comparisons of independent categorical data, Fisher’s exact test was performed; for comparisons of independent metrical data, a Mann-Whitney U test was performed; for comparisons of paired metrical data, a Wilcoxon signed-rank test was performed, and for correlation analyses, a Pearson correlation test was performed. For comparisons of LE subgroups with the controls, a Kruskal-Wallis test was additionally performed. Correlation analyses of patients’ volumes with clinical parameters and antibody concentrations were performed using all available absolute volumes (entire LE group) and normalised volumes (LE subgroups) at all available time points. A probability ( p) value
JNNP Online First, published on September 2, 2014 as 10.1136/jnnp-2014-307875 Epilepsy
RESEARCH PAPER
Automated volumetry of the mesiotemporal structures in antibody-associated limbic encephalitis Jan Wagner,1,2 Juri-Alexander Witt,1 Christoph Helmstaedter,1 Michael P Malter,1,3 Bernd Weber,1,2,4 Christian E Elger1,2,4 ▸ Additional material is published online only. To view please visit the journal online (http://dx.doi.org/10.1136/ jnnp-2014-307875). 1
Department of Epileptology, University of Bonn, Bonn, Germany 2 Department of NeuroCognition/Imaging, Life & Brain Center, Bonn, Germany 3 Department of Neurology, Marien-Krankenhaus, Bergisch Gladbach, Germany 4 Center for Economics and Neuroscience, University of Bonn, Bonn, Germany Correspondence to Dr Jan Wagner, Department of Epileptology, University of Bonn, Sigmund-Freud-Str. 25, Bonn D-53127, Germany; jan. [email protected] Received 13 February 2014 Revised 31 July 2014 Accepted 12 August 2014
ABSTRACT Objective Limbic encephalitis (LE) is an autoimmune mediated disease leading to temporal lobe epilepsy, mnestic and psychiatric symptoms. In recent years, several LE subforms defined by serum antibody findings have been described. MRI usually shows volume changes of the amygdala and hippocampus. However, studies quantifying longitudinal volume changes in the acute disease stage are lacking. Methods The aim of this retrospective observational study was to evaluate and quantify these volume changes by applying a fully automated volumetric approach to serial MRIs of 28 patients with antibody-associated LE. The results were compared with those of 28 age-matched and gender-matched healthy controls and analysed separately for the different antibody profiles and correlated with clinical parameters. Antibody profile analyses were exploratory due to the relatively small sample sizes. Results We found distinct volumetric and clinical courses depending on the associated antibody. While LE associated with voltage-gated potassium channel-complex antibodies (VGKC-LE) showed highly significant larger volumes of both the amygdala and the hippocampus within the first 12 months after disease onset, LE associated with glutamic acid decarboxylase antibodies (GAD-LE) only displayed greater amygdala volumes at this disease stage. Both subgroups showed a reduction of the amygdala and hippocampus volumes during follow-up with higher volume changes in VGKC-LE. Conclusions These differences in the volumetric evolution corresponded to distinct clinical courses in terms of a more severe initial symptomatology regarding seizure, mnestic and psychiatric disturbances in VGKC-LE, which improved rapidly, corresponding to the evolution of the volumetric changes. In contrast to this, patients with GADLE were less severely affected at disease onset, showing a more unmodulated and chronic disease course during follow-up.
INTRODUCTION
To cite: Wagner J, Witt J-A, Helmstaedter C, et al. J Neurol Neurosurg Psychiatry Published Online First: [please include Day Month Year] doi:10.1136/jnnp2014-307875
Limbic encephalitis (LE) is an autoimmunemediated disease leading to temporal lobe epilepsy, mnestic deficits and psychiatric symptoms.1 2 It was first described in the 1960s as a paraneoplastic syndrome caused by inflammation in limbic structures in adults.3 4 Various onconeural antibodies, which are biomarkers for these paraneoplastic syndromes, have been discovered in the following decades.5 However, in recent years, non-paraneoplastic forms of LE have been increasingly recognised, associated with antibodies against glutamic acid decarboxylase (GAD) and the voltage-gated potassium channel
(VGKC)-complex.6–9 These non-paraneoplastic forms have a better prognosis, but the outcome seems to differ between the two subgroups depending on the associated antibody. While patients with VGKC-complex-associated LE (VGKC-LE) mostly become seizure-free and show normalised antibody concentrations after immunotherapy, GAD-associated LE (GAD-LE) often displays a non-remitting course with antibody and seizure persistence.6 8 10 MRI in LE shows signal and volume changes of the mesiotemporal structures. However, studies quantifying volume changes in LE are scarce. In a recently published study, Irani et al11 found smaller volumes of the whole brain and hippocampus (HC) in VGKC-LE compared to healthy controls. However, MRI was performed in the convalescent phase of the disease and neither amygdala (AM) volumes nor longitudinal volume changes were investigated. The aim of the present study was to evaluate and quantify longitudinal volume changes of AM and HC in the acute and subacute disease stages of antibody-associated LE compared to healthy controls using a fully automated volumetric approach. Furthermore, results were analysed depending on the associated antibody and correlated with clinical parameters (eg, seizure outcome, mnestic and psychiatric symptoms). In doing so, we aimed at addressing the following questions: (1) Is there a difference in AM and HC volumes between patients with LE and healthy participants? (2) How is the temporal evolution of the volumetric changes? (3) Do volumetric changes correlate with clinical parameters? (4) Can we find distinct volumetric and clinical results depending on the associated antibody?
MATERIALS AND METHODS Study groups and MRI examinations We retrospectively studied all patients diagnosed with antibody-associated LE presenting at the Department of Epileptology, University of Bonn, from 1 January 2006 to 31 August 2012. LE was diagnosed based on the features of (1) limbic signs and symptoms, which manifested themselves in adolescence or adulthood (≥one of the following: seizures of temporal semiology, disturbance of episodic memory, psychiatric symptoms with affective and/or anxiety disturbances) and (2) presence of serum antibodies associated with LE (ie, onconeural, VGKC-complex, GAD). Serum antibody testing for GAD, onconeural and VGKC-complex antibodies was performed as described previously.12 Antibodies against leucine-
al. J Neurol Neurosurg 2014;0:1–8. doi:10.1136/jnnp-2014-307875 Copyright Article author (orWagner theirJ, etemployer) 2014.Psychiatry Produced by BMJ Publishing Group Ltd under licence.
1
Downloaded from jnnp.bmj.com on September 4, 2014 - Published by group.bmj.com
Epilepsy rich, glioma inactivated 1 protein (LGI1) and contactin-associated protein-2 (CASPR2) were detected by indirect immunofluorescence using formalin fixed HEK293 cells containing membrane bound LGI1 or CASPR2.13 To allow for an evaluation of the volume changes in the acute disease stage and to assess all included patients at the same disease period, we only included patients whose first MRI including a three-dimensional (3D) T1-weighted volume data set was performed within the first 12 months after LE onset. LE onset was defined as the time point of the first symptoms suggestive of LE (seizures and/or psychiatric and/or mnestic disturbances). If available, we furthermore analysed up to two follow-up MRIs each six to 12 months after the preceding MRI scan to assess the course of the volume changes within the first 36 months of the disease. The control group was assembled from a pre-existing in-house database consisting of 1262 healthy participants with no neurological disorder. Age-matching and gender-matching with the LE group was achieved by building matched pairs for each individual patient. The MRIs of the selected controls were thoroughly inspected and were free of lesions especially in the mesiotemporal region. We did not exclude controls with unspecific extratemporal lesions on MRI (eg, microangiopathy). As follow-up MRI examinations with resembling time intervals were not available for the control group, the control group for the patients’ follow-up MRIs consisted of the corresponding matched participants (ie, for each missing patient, the corresponding matched participant was excluded). All included patients and healthy participants underwent at least one MRI examination including a 3D T1-weighted volume data set using the same 3T MRI scanner (Magnetom Trio, Siemens, Erlangen, Germany) with the same sequence parameters in all participants (MP-RAGE, voxel size 1×1×1 mm, repetition time 1570 ms, echo time 3.42 ms, flip angle 15°, field of view 256 mm×256 mm).
Statistical analysis Statistical analyses were performed using SPSS Statistics V.21.0 for Mac OS X (IBM, Armonk, New York, USA). All values throughout this report are given as median unless otherwise stated. For statistical comparisons of independent categorical data, Fisher’s exact test was performed; for comparisons of independent metrical data, a Mann-Whitney U test was performed; for comparisons of paired metrical data, a Wilcoxon signed-rank test was performed, and for correlation analyses, a Pearson correlation test was performed. For comparisons of LE subgroups with the controls, a Kruskal-Wallis test was additionally performed. Correlation analyses of patients’ volumes with clinical parameters and antibody concentrations were performed using all available absolute volumes (entire LE group) and normalised volumes (LE subgroups) at all available time points. A probability ( p) value
