'Hippocampal innate inflammatory gliosis only' in pharmacoresistant temporal lobe epilepsy.

Drug-resistant mesial-temporal lobe epilepsy is a devastating disease with seizure onset in the hippocampal formation. A fraction of hippocampi samples from epilepsy-surgical procedures reveals a peculiar histological pattern referred to as 'gliosis only' with unresolved pathogenesis and enigmatic sequelae. Here, we hypothesize that 'gliosis only' represents a particular syndrome defined by distinct clinical and molecular characteristics. We curated an in-depth multiparameter integration of systematic clinical, neuropsychological as well as neuropathological analysis from a consecutive cohort of 627 patients, who underwent hippocampectomy for drug-resistant temporal lobe epilepsy. All patients underwent either classic anterior temporal lobectomy or selective amygdalohippocampectomy. On the basis of their neuropathological exam, patients with hippocampus sclerosis and 'gliosis only' were characterized and compared within the whole cohort and within a subset of matched pairs. Integrated transcriptional analysis was performed to address molecular differences between both groups. 'Gliosis only' revealed demographics, clinical and neuropsychological outcome fundamentally different from hippocampus sclerosis. 'Gliosis only' patients had a significantly later seizure onset (16.3 versus 12.2 years, P = 0.005) and worse neuropsychological outcome after surgery compared to patients with hippocampus sclerosis. Epilepsy was less amendable by surgery in 'gliosis only' patients, resulting in a significantly worse rate of seizure freedom after surgery in this subgroup (43% versus 68%, P = 0.0001, odds ratio = 2.8, confidence interval 1.7-4.7). This finding remained significant after multivariate and matched-pairs analysis. The 'gliosis only' group demonstrated pronounced astrogliosis and lack of significant neuronal degeneration in contrast to characteristic segmental neuron loss and fibrillary astrogliosis in hippocampus sclerosis. RNA-sequencing of gliosis only patients deciphered a distinct transcriptional programme that resembles an innate inflammatory response of reactive astrocytes. Our data indicate a new temporal lobe epilepsy syndrome for which we suggest the term 'Innate inflammatory gliosis only'. 'Innate inflammatory gliosis only' is characterized by a diffuse gliosis pattern lacking restricted hippocampal focality and is poorly controllable by surgery. Thus, 'innate inflammatory gliosis only' patients need to be clearly identified by presurgical examination paradigms of pharmacoresistant temporal lobe epilepsy patients; surgical treatment of this subgroup should be considered with great precaution. 'Innate inflammatory gliosis only' requires innovative pharmacotreatment strategies.

Preoperative and postoperative memory in epilepsy patients with 'gliosis only' versus hippocampal sclerosis: a matched case-control study.

BACKGROUND: Gliosis only (GO) and hippocampal sclerosis (HS) are distinct histopathological entities in mesial temporal lobe epilepsy. This study explores whether this distinction also exists on a functional level when evaluating pre- and postoperative memory. METHODS: Using a retrospective matched case-control study design, we analysed verbal and visual memory performance in 49 patients with GO and 49 patients with HS before and one year after elective surgery. RESULTS: Clinical differences were evident with a later age at seizure onset (18±12 vs 12±9 years) and fewer postoperative seizure-free patients in the GO group (63% vs 82%). Preoperatively, group and individual-level data demonstrated that memory impairments were less frequent, less severe and relatively non-specific in patients with GO compared with HS. Postoperatively, verbal memory declined in both groups, particularly after left-sided resections, with more significant losses in patients with GO. Factoring in floor effects, GO was also associated with more significant visual memory loss, particularly after left resections. CONCLUSIONS: Compared with HS, GO is characterised by (1) a later onset of epilepsy, (2) less pronounced and more non-specific memory impairments before surgery, (3) a less successful surgical outcome and (4) a more significant memory decline after surgery. Overall, our results regarding cognition provide further evidence that GO and HS are distinct clinical entities. Functional integrity of the hippocampus appears higher in GO, as indicated by a better preoperative memory performance and worse memory outcome after surgery. The different risk-benefit ratios should be considered during presurgical patient counselling.

Permanent loss of independence in adult febrile-infection-related epilepsy syndrome survivors: an underestimated and unsolved challenge.

BACKGROUND AND PURPOSE: Febrile-infection-related epilepsy syndrome (FIRES) is an exceedingly rare and devastating subtype of new-onset refractory status epilepticus, which causes refractory epilepsy and permanent neurocognitive impairment. METHODS: This was a long-term follow-up of adult FIRES survivors treated between 2005 and 2018 as part of the EpiCARE initiative, a European Reference Network for rare and complex epilepsies. Clinical, electroencephalography, imaging and functional outcome measures are described using the Scores of Independence for Neurologic and Geriatric Rehabilitation, the modified Rankin Scale and the Global Assessment of Severity of Epilepsy Scale. RESULTS: Six patients with refractory epilepsy following FIRES were evaluated. Despite general improvement after intensive care unit discharge, disease severity was still high at follow-up in all patients. The functional outcome, as assessed by the modified Rankin Scale, was moderately impaired in 2/6 patients. In contrast, the Scores of Independence for Neurologic and Geriatric Rehabilitation indicated a loss of independence in 5/6, serious problems in memory and planning/problem-solving in 4/6 and serious attentional problems in 3/6 patients. CONCLUSIONS: Febrile-infection-related epilepsy syndrome survivors may regain vital functions and mobility but experience a significant loss of independence and participation due to recurring seizures, structural brain damage and neurocognitive decline. Minimization of disastrous outcomes through the systematic evaluation of rescue therapies within a network of specialized centres is crucial.

The efficacy of a short-term multidisciplinary epilepsy program.

RATIONALE: Epilepsy is more than having seizures. Therefore, specialized epilepsy centers in Germany offer multidisciplinary programs for inpatients with pharmacoresistant epilepsies. This monocentric study evaluated the efficacy of a short-term program that is based on a biopsychosocial model of health and conceptualized by occupational therapists, physical therapists, neuropsychologists, and social workers. METHODS: Of the 1573 patients treated between 2008 and 2014, 1339 were rated using a 7-tiered predefined category system. Outcome domains are compliance, affect, activity, autonomy, communication, fine motor skills, and mobility. Based on a total score, the patients were classified as impaired, functional, or highly functional. Functionality at baseline and changes after the treatment were analyzed and related to demographics, medical, and neuropsychological data. RESULTS: At baseline, 80.8% of the patients were rated as impaired according to the total score. Impairments were predominantly observed in the domains affect, autonomy, and communication. A better total score at baseline was significantly related to a better neuropsychological functioning and a lower number of concurrent antiepileptic drugs. After the intervention 50.3% of the patients showed significant improvements regarding the total score. Compliance, activity, and affect were the most responsive domains. CONCLUSION: This study provides promising results with regard to the efficacy of a short-term multidisciplinary epilepsy program. Positive effects could be achieved referring to compliance, activity, and affect. The findings support the relevance of such programs. Subsequent research should focus on the transfer to everyday life.

Interictal blood-brain barrier dysfunction in piriform cortex of people with epilepsy.

OBJECTIVE: The piriform cortex is considered to be highly epileptogenic. Its resection during epilepsy surgery is a predictor for postoperative seizure freedom in temporal lobe epilepsy. Epilepsy is associated with a dysfunction of the blood-brain barrier. We investigated blood-brain barrier dysfunction in the piriform cortex of people with temporal lobe epilepsy using quantitative T1-relaxometry. METHODS: Gadolinium-based contrast agent was administered ictally and interictally in 37 individuals before undergoing quantitative T1-relaxometry. Postictal and interictal images were co-registered, and subtraction maps were created as biomarkers for peri-ictal (∆qT1interictal-postictal) and interictal (∆qT1noncontrast-interictal) blood-brain barrier dysfunction. Values were extracted for the piriform cortex, hippocampus, amygdala, and the whole cortex. RESULTS: In temporal lobe epilepsy (n = 14), ∆qT1noncontrast-interictal was significantly higher in the piriform cortex than in the whole cortex (p = 0.02). In extratemporal lobe epilepsy (n = 23), ∆qT1noncontrast-interictal was higher in the hippocampus than in the whole cortex (p = 0.05). Across all individuals (n = 37), duration of epilepsy was correlated with ∆qT1noncontrast-interictal (ß = 0.001, p < 0.001) in all regions, while the association was strongest in the piriform cortex. Impaired verbal memory was associated with ∆qT1noncontrast-interictal only in the piriform cortex (p = 0.04). ∆qT1interictal-postictal did not show differences in any region. INTERPRETATION: Interictal blood-brain barrier dysfunction occurs in the piriform cortex in temporal lobe epilepsy. This dysfunction is linked to longer disease duration and worse cognitive deficits, emphasizing the central role of the piriform cortex in the epileptogenic network of temporal lobe epilepsy.

All's well that ends well? Long-term course of a patient with anti-amphiphysin associated limbic encephalitis.

Anti-amphiphysin associated limbic encephalitis (LE) is a paraneoplastic autoimmune disorder. The initial clinical presentation features seizures, cognitive and neuropsychiatric symptoms. We present the case of a 25-year-old female patient hospitalized after four consecutive tonic-clonic seizures, followed by confusion, psychotic symptoms, nonconvulsive seizure series, and severe global amnesia. Diagnostic workup revealed anti-amphiphysin associated LE without a tumor. MRI and PET indicated inflammatory processes affecting the bilateral mesial temporal structures more pronounced on the left side. Antiseizure medication, benzodiazepines, and immunotherapy resulted in rapid seizure cessation. Subsequent MRI and PET indicated left hippocampal sclerosis and a left mesial temporal hypometabolism. Executive dysfunction resolved in the following weeks. Global amnesia persisted for almost three months. Two years later, episodic memory was normal with residual visual memory impairments. While this patient's seizure and cognitive outcome has been favorable, behavioral problems persisted long after disease onset. The persisting behavioral problems and subsequent MRI evidence (13 years after onset) of a swollen right amygdala indicated a possible relapse. This case report illustrates the importance of early diagnosis of LE for best clinical management. Antiseizure medication and immunotherapy led to seizure freedom and almost complete recovery of cognition. However, long-lasting neuropsychiatric symptoms and possible recurrent inflammation highlight the need for a multimodal long-term monitoring of such patients to rule out a relapse.

Resection of piriform cortex predicts seizure freedom in temporal lobe epilepsy.

OBJECTIVE: Transsylvian selective amygdalo-hippocampectomy (tsSAHE) represents a generally recognized surgical procedure for drug-resistant mesial temporal lobe epilepsy (mTLE). Although postoperative seizure freedom can be achieved in about 70% of tsSAHE, there is a considerable amount of patients with persisting postoperative seizures. This might partly be explained by differing extents of resection of various tsSAHE target volumes. In this study we analyzed the resected proportions of hippocampus, amygdala as well as piriform cortex in regard of postoperative seizure outcome. METHODS: Between 2012 and 2017, 82 of 103 patients with mTLE who underwent tsSAHE at the authors' institution were included in the analysis. Resected proportions of hippocampus, amygdala and temporal piriform cortex as target structures of tsSAHE were volumetrically assessed and stratified according to favorable (International League Against Epilepsy (ILAE) class 1) and unfavorable (ILAE class 2-6) seizure outcome. RESULTS: Patients with favorable seizure outcome revealed a significantly larger proportion of resected temporal piriform cortex volumes compared to patients with unfavorable seizure outcome (median resected proportional volumes were 51% (IQR 42-61) versus (vs.) 13 (IQR 11-18), P = 0.0001). Resected proportions of hippocampus and amygdala did not significantly differ for these groups (hippocampus: 81% (IQR 73-88) vs. 80% (IQR 74-92) (P = 0.7); amygdala: 100% (IQR 100-100) vs. 100% (IQR 100-100) (P = 0.7)). INTERPRETATION: These results strongly suggest temporal piriform cortex to constitute a key target resection volume to achieve seizure freedom following tsSAHE.

Surgery for temporal lobe epilepsy in the elderly: Improving quality of life despite cognitive impairment.

INTRODUCTION: Temporal lobe epilepsy (TLE) surgery is still underutilized, especially in the elderly population because of concerns related to postoperative complication rate and cognitive deterioration. The aim of the study was to evaluate surgical data, quality of life and neuropsychological outcome in elderly patients, who underwent resective surgery for drug resistant TLE. METHODS AND MATERIALS: All patients underwent standardized presurgical assessment including clinical, neuroradiological, neuropsychological, and EEG examination. Elderly were considered all patients being 50 years or above (mean 56 yr., range 50-71 yr.). Neuropsychology was assessed before and after surgery, health-related quality of life (HRQOL) only after surgery. RESULTS: A total of 94 consecutive elderly patients were analyzed. Temporo-mesial resections were performed in 85 patients (90 %). Seizure outcome was available in all patients with a mean follow-up of 5.2 years (1.2-19 ± 3.75 years). 57 patients (60.6 %) were completely seizure free (ILAE 1). The overall morbidity was 10 % including 5 surgical complications and 5 permanent neurological deficits. Neuropsychological assessments in 60 patients showed considerable preoperative impairment, losses in different domains in 25-45 % and gains in about 25 % of the patients. Postoperative HRQOL data was available in 75 patients, revealing significant increase of HRQOL in all domains. Complete seizure freedom was the strongest predictor for postoperative HRQOL (p < 0.001). CONCLUSION: Surgery for drug resistant temporal lobe epilepsy is a feasible option for elderly patients as seizure control rates are comparable to the younger population. The acceptable rate of permanent neurological deficits and relevant improvements in quality of life, despite considerable postoperative cognitive impairment, justify surgical resection in properly selected elderly patients.