Michael P. Malter

Incidence and Mechanisms of Cardiorespiratory Arrests in Epilepsy Monitoring Units (MORTEMUS): A Retrospective Study.

BACKGROUND Sudden unexpected death in epilepsy (SUDEP) is the leading cause of death in people with chronic refractory epilepsy. Very rarely, SUDEP occurs in epilepsy monitoring units, providing highly informative data for its still elusive pathophysiology. The MORTEMUS study expanded these data through comprehensive evaluation of cardiorespiratory arrests encountered in epilepsy monitoring units worldwide. METHODS Between Jan 1, 2008, and Dec 29, 2009, we did a systematic retrospective survey of epilepsy monitoring units located in Europe, Israel, Australia, and New Zealand, to retrieve data for all cardiorespiratory arrests recorded in these units and estimate their incidence. Epilepsy monitoring units from other regions were invited to report similar cases to further explore the mechanisms. An expert panel reviewed data, including video electroencephalogram (VEEG) and electrocardiogram material at the time of cardiorespiratory arrests whenever available. FINDINGS 147 (92%) of 160 units responded to the survey. 29 cardiorespiratory arrests, including 16 SUDEP (14 at night), nine near SUDEP, and four deaths from other causes, were reported. Cardiorespiratory data, available for ten cases of SUDEP, showed a consistent and previously unrecognised pattern whereby rapid breathing (18-50 breaths per min) developed after secondary generalised tonic-clonic seizure, followed within 3 min by transient or terminal cardiorespiratory dysfunction. Where transient, this dysfunction later recurred with terminal apnoea occurring within 11 min of the end of the seizure, followed by cardiac arrest. SUDEP incidence in adult epilepsy monitoring units was 5·1 (95% CI 2·6-9·2) per 1000 patient-years, with a risk of 1·2 (0·6-2·1) per 10,000 VEEG monitorings, probably aggravated by suboptimum supervision and possibly by antiepileptic drug withdrawal. INTERPRETATION SUDEP in epilepsy monitoring units primarily follows an early postictal, centrally mediated, severe alteration of respiratory and cardiac function induced by generalised tonic-clonic seizure, leading to immediate death or a short period of partly restored cardiorespiratory function followed by terminal apnoea then cardiac arrest. Improved supervision is warranted in epilepsy monitoring units, in particular during night time. FUNDING Commission of European Affairs of the International League Against Epilepsy.

Antibodies to glutamic acid decarboxylase define a form of limbic encephalitis.

Antibodies to glutamic acid decarboxylase (GAD) have been described in a few patients with temporal lobe epilepsies consistent with limbic encephalitis (LE). We studied a cohort of patients with recent‐onset temporal lobe epilepsy caused by LE to test for GAD antibody positivity and response to immunotherapies.

Neuropsychological course of voltage-gated potassium channel and glutamic acid decarboxylase antibody related limbic encephalitis

Autoantibodies (abs) to glutamic acid decarboxylase (GAD) and to voltage‐gated potassium channels (VGKC) induce distinct courses of limbic encephalitis, related to MRI findings, seizure outcome and cognition.

Diagnostic value of CSF findings in antibody-associated limbic and anti-NMDAR-encephalitis

PURPOSE In people with suspected inflammatory CNS disease, cerebrospinal fluid (CSF) is commonly analyzed. Antibody-associated limbic encephalitis (ab-LE) and anti-NMDAR-encephalitis are recognized as two major syndromes of autoimmune epilepsies. Here, we investigated the diagnostic value of CSF findings in these two entities. METHODS We reviewed patients from our tertiary epilepsy centre with ab-LE and anti-NMDAR-encephalitis in whom CSF examination including oligoclonal bands (OCB) was performed. Ab-LE patients were subdivided according to antibodies (voltage-gated potassium channels, VGKC; glutamic acid decarboxylase, GAD) or presence of onconeural antibodies/presence of tumour into three groups: VGKC-LE, GAD-LE or paraneoplastic LE (PLE). As controls, patients with CSF investigations in whom autoimmune origin was initially assumed but not confirmed later on were included. In addition, a review of published ab-LE and anti-NMDAR-encephalitis cases with reported CSF data was performed. RESULTS 55 ab-LE (23 VGKC-LE, 25 GAD-LE, 7 PLE) and 14 anti-NMDAR-encephalitis patients were identified at our centre. OCB were significantly more frequent in ab-LE and anti-NMDAR-encephalitis than in controls. Literature review identified 150 ab-LE and 95 NMDAR cases. Analysis of pooled data confirmed that presence of OCB was significantly more frequent in ab-LE and anti-NMDAR-encephalitis (especially in people with GAD-LE and anti-NMDAR encephalitis) as compared to controls. Sensitivity and specificity of OCB in the pooled ab-LE and anti-NMDAR-encephalitis patients was 34% and 96%, respectively. In patients with ab-LE and anti-NMDAR-encephalitis, the likelihood of OCB in CSF was 8.5-fold higher as compared to controls. Furthermore, in the pooled ab-LE and anti-NMDAR-encephalitis patients, cell counts in CSF were more frequently elevated (especially in those with anti-NMDAR encephalitis) than in controls, whereas protein content of CSF was not different between the groups. CONCLUSION OCB, and to a lesser extent cell counts in CSF, appear to be helpful additional CSF markers in the diagnostic evaluation of people presenting with a constellation suggestive for GAD-LE, PLE and anti-NMDAR-encephalitis, prompting subsequent analysis of specific antibodies.

Automated volumetry of the mesiotemporal structures in antibody-associated limbic encephalitis

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 GAD-LE were less severely affected at disease onset, showing a more unmodulated and chronic disease course during follow-up.

Quantitative FLAIR analysis indicates predominant affection of the amygdala in antibody-associated limbic encephalitis

Limbic encephalitis is an autoimmune‐mediated disease leading to temporal lobe epilepsy, mnestic deficits, and affective disturbances. Magnetic resonance imaging (MRI) usually shows signal and volume changes of the temporomesial structures. However, these abnormalities may be subtle, thereby hampering the diagnosis by conventional visual assessment. In the present study we evaluated the diagnostic value of a fully automated MRI postprocessing technique in limbic encephalitis and hippocampal sclerosis.

Treatment of immune-mediated temporal lobe epilepsy with GAD antibodies

PURPOSE Temporal lobe epilepsy with antibodies (abs) against the glutamic acid decarboxylase 65 isoform (GAD-TLE) is known as an immune-mediated neurological syndrome. Here we evaluate the therapy response to various immunotherapies and epilepsy surgery in this syndrome. METHOD All patients with GAD-TLE and follow-up data and stored serum and CSF samples, identified and treated at the Bonn centre from 2002 to 2010, were studied retrospectively. Seizure freedom for ≥1 year and reduction of ≥50%, i.e. therapy response, were assessed. GAD-ab titres and neuropsychological performances were documented prior and after individual interventions. RESULTS Thirteen patients with GAD-TLE were identified with the following seizure responses: corticosteroids (5 responders out of 11 treated patients); i.v. immunoglobulins (1/5), apheresis therapy (1/8); and natalizumab (1/1), selective amygdala-hippocampectomy (2/3). None of the patients achieved sustained seizure freedom apart from one patient. This patient was on antiepileptic drug treatment after discontinuation of immunotherapy. CONCLUSION The seizure response to immunotherapies in patients with GAD-TLE was poor. Corticosteroids were the most effective regarding seizure response. Especially the poor effects of apheresis therapies support the idea that GAD-abs are not directly pathogenic. None of three patients was seizure-free after temporal lobe surgery suggesting that GAD-TLE patients respond worse than others to this type of intervention. Our results reflect the chronic course of the disease with low likelihood for patients with GAD-TLE to attain long-term seizure freedom.

Suspected new-onset autoimmune temporal lobe epilepsy with amygdala enlargement.

Recent reports define temporal lobe epilepsy with amygdala enlargement (TLE‐AE) as a distinct electroclinical syndrome comparable to TLE with hippocampal sclerosis. In this retrospective observational study, we present the largest consecutive series of patients with new‐onset TLE‐AE to date and describe clinical characteristics and seizure outcome, and we aim to explore underlying autoimmune mechanisms within this syndrome.

The importance of early immunotherapy in patients with faciobrachial dystonic seizures

Faciobrachial dystonic seizures (FBDS) are the first adult-onset autoantibody-mediated epilepsy. Thompson et al. describe 103 patients with FBDS, and show that seizures are responsive to immunotherapy, with early seizure cessation reducing long-term disability and preventing cognitive impairment. Potential pathogenic mechanisms include complement fixation and LGI1-ADAM22 complex internalisation.

Surgical management and long-term seizure outcome after epilepsy surgery for different types of epilepsy associated with cerebral cavernous malformations

Precise outcome data about the surgical therapy of cerebral cavernous malformation (CCM)–associated epilepsy is scarce regarding different epilepsy types, surgical approach, and outcome. Long‐term outcome in patients with CCM‐associated epilepsy is analyzed in a large single‐center series.