Association of biallelic RFC1 expansion with early-onset Parkinson's disease.

BACKGROUND AND PURPOSE: The biallelic repeat expansion (AAGGG)exp in the replication factor C subunit 1 gene (RFC1) is a frequent cause of cerebellar ataxia, neuropathy and vestibular areflexia syndrome (CANVAS) as well as late-onset ataxia. The clinical spectrum of RFC1 disease has expanded since the first identification of biallelic (AAGGG)exp and includes now various nonclassical phenotypes. Biallelic (AAGGG)exp in RFC1 in patients with clinically confirmed Parkinson's disease (PD) has recently been found. METHODS: A nationwide cohort of 273 Finnish patients with early-onset PD was examined for the biallelic intronic expansion in RFC1. The expansion (AAGGG)exp was first screened using extra long polymerase chain reactions (Extra Large-PCRs) and flanking multiplex PCR. The presence of biallelic (AAGGG)exp was then confirmed by repeat-primed PCR and, finally, the repeat length was determined by long-read sequencing. RESULTS: Three patients were found with the biallelic (AAGGG)exp in RFC1 giving a frequency of 1.10% (0.23%-3.18%; 95% confidence interval). The three patients fulfilled the diagnostic criteria of PD, none of them had ataxia or neuropathy, and only one patient had a mild vestibular dysfunction. The age at onset of PD symptoms was 40-48 years and their disease course had been unremarkable apart from the early onset. CONCLUSIONS: Our results suggest that (AAGGG)exp in RFC1 is a rare cause of early-onset PD. Other populations should be examined in order to determine whether our findings are specific to the Finnish population.

High-mobility group box 1 as a predictive biomarker for drug-resistant epilepsy: A proof-of-concept study.

Currently no sensitive and specific biomarkers exist to predict drug-resistant epilepsy. We determined whether blood levels of high-mobility group box 1 (HMGB1), a mediator of neuroinflammation implicated in drug-resistant epilepsies, identifies patients with drug-resistant seizures. Patients with drug-resistant epilepsy express significantly higher levels of blood HMGB1 than those with drug-responsive, well-controlled seizures and healthy controls. No correlation existed between blood HMGB1 levels and total pretreatment seizure count or days since last seizure at new epilepsy diagnosis, indicating that blood HMGB1 does not solely reflect ongoing seizures. HMGB1 distinguishes with high specificity and selectivity drug-resistant versus drug-responsive patients. This protein therefore has potential clinical utility to act as a biomarker for predicting response to therapy, which should be addressed in prospective clinical studies.

The production of IL-6 in acute epileptic seizure: A video-EEG study.

Experimental and clinical reports highlight the role of cytokines in pathophysiological processes in underpinning epilepsy, but the clinical data remains somewhat limited. The levels of Interleukin (IL)-6 were measured in serum from 49 patients with refractory epilepsy [temporal lobe epilepsy (TLE, n=23), extratemporal lobe epilepsy (XLE, n=22), and idiopathic generalized epilepsy (IGE, n=4)] before and after the first verified seizure (IS; index seizure) during inpatient video-electroencephalographic (VEEG) monitoring. The levels of IL-6 increased significantly at all time points between 3h and 24h after the IS compared to the baseline. IL-6 concentrations were significantly higher at the 3h and 6h time point after tonic-clonic seizures (TCS) compared to the situation with simple partial and complex partial seizures. An IS duration longer than 100s, low baseline IL-6 level and <10 seizures/month in patients with TLE were associated with an increase in IL-6 concentrations during the 24h after the IS. In patients with TLE, the maximum change in IL-6 levels after IS was significantly higher than in XLE. If the baseline level of IL-6 was low (under 5pg/ml), seizures induced a significant elevation in both absolute and relative values in TLE patients but not in XLE. In patients with ≤10 seizures per month during the last year, the maximum change was higher than in patients with >10 seizures. If the total seizure burden during registration was ≥100s, the IL-6 increase was significantly higher than if it were under 100s. The results of this study highlight the complexity of factors involved in the seizure induced production of the inflammatory cytokine, IL-6. The major factor is the epilepsy type i.e. increased production of IL-6 in TLE compared to XLE. The response to a single seizure in TLE is dependent on the previous seizure frequency and the baseline IL-6 concentration.

Comparative effectiveness of eight antiepileptic drugs in adults with focal refractory epilepsy: the influence of age, gender, and the sequence in which drugs were introduced onto the market.

The first objective was to determine the long-term retention rate of eight antiepileptic drugs (AEDs) commonly used as adjunctive therapy in adults with focal refractory epilepsy. Second, we assessed the effects of age and gender on retention rates. Third, we examined if the retention rate could be influenced by the sequence in which the AEDs had entered the market. Patients with focal refractory epilepsy treated with any of the eight AEDs in Tampere University Hospital were identified retrospectively (N = 507). Retention rates were evaluated with the Kaplan-Meier method. Follow-up started at the first date of treatment and each individual was followed a maximum of 36 months. We calculated the following 3-year retention rates: lacosamide 77.1% (N = 137), lamotrigine 68.3% (N = 177), levetiracetam 66.7% (N = 319), clobazam 65.6% (N = 130), topiramate 61.6% (N = 178), zonisamide 60.4% (N = 103), pregabalin 54.6% (N = 127), and gabapentin 40.2% (N = 66). Lacosamide, levetiracetam, and clobazam were the most effective AEDs in the elderly. The retention rate for pregabalin was higher in males (65%) than females (51%) whereas females had higher retention rates for both topiramate (72 vs. 58%) and zonisamide (67 vs. 57%). The retention rate was influenced by the sequence in which these AEDs entered the market. We provide important information about practical aspects of these eight AEDs, revealing that there are differences in their effectiveness as adjunctive treatment for focal refractory epilepsy. Most importantly, the retention rate appears to be influenced by the sequence in which these AEDs were introduced onto the market.

Molecular isoforms of high-mobility group box 1 are mechanistic biomarkers for epilepsy.

Approximately 30% of epilepsy patients do not respond to antiepileptic drugs, representing an unmet medical need. There is evidence that neuroinflammation plays a pathogenic role in drug-resistant epilepsy. The high-mobility group box 1 (HMGB1)/TLR4 axis is a key initiator of neuroinflammation following epileptogenic injuries, and its activation contributes to seizure generation in animal models. However, further work is required to understand the role of HMGB1 and its isoforms in epileptogenesis and drug resistance. Using a combination of animal models and sera from clinically well-characterized patients, we have demonstrated that there are dynamic changes in HMGB1 isoforms in the brain and blood of animals undergoing epileptogenesis. The pathologic disulfide HMGB1 isoform progressively increased in blood before epilepsy onset and prospectively identified animals that developed the disease. Consistent with animal data, we observed early expression of disulfide HMGB1 in patients with newly diagnosed epilepsy, and its persistence was associated with subsequent seizures. In contrast with patients with well-controlled epilepsy, patients with chronic, drug-refractory epilepsy persistently expressed the acetylated, disulfide HMGB1 isoforms. Moreover, treatment of animals with antiinflammatory drugs during epileptogenesis prevented both disease progression and blood increase in HMGB1 isoforms. Our data suggest that HMGB1 isoforms are mechanistic biomarkers for epileptogenesis and drug-resistant epilepsy in humans, necessitating evaluation in larger-scale prospective studies.

The concentration of cell-free DNA in video-EEG patients is dependent on the epilepsy syndrome and duration of epilepsy.

OBJECTIVE: Cell-free DNA (cf-DNA) is a marker of inflammation and cell death. The purpose of the present study was to analyze the role of cf-DNA as a putative biomarker in refractory epilepsy. METHODS: Baseline concentration of cf-DNA was measured in the serum of 51 carefully evaluated refractory epilepsy patients undergoing video-EEG monitoring. Epilepsy was classified based on seizure semiology, patient history, and imaging findings. Majority of the patients (47) had focal epilepsy. The association of the concentration cf-DNA with different clinical determinants was analyzed. 250 healthy individuals served as control subjects. RESULTS: The mean baseline concentration of cf-DNA was lower in patients with extra temporal lobe epilepsy (XTLE) compared to control subjects (0.72 µg/ml vs. 0.80 µg/ml; p = 0.001). The difference in concentration of cf-DNA between patients with temporal lobe epilepsy (TLE) and control subjects was not significant. The maximum concentration of cf-DNA after baseline measurement was significantly lower in patients with duration of epilepsy ≥ 18 years compared to those with duration of epilepsy < 18 years (0.022 µg/ml vs. 0.031 µg/ml; p = 0.044). The maximum concentration of cf-DNA was higher in patients with body mass index (BMI) ≥ 25 compared to those with BMI < 25 (0.004 µg/ml vs. 0.041 µg/ml; p = 0.006). DISCUSSION: The difference in cf-DNA concentration between patients with XTLE and control subjects strengthens the previous observations of the importance of epilepsy type with regard of different biomarkers.

Immunological perspectives of temporal lobe seizures.

The temporal lobes are affected in many different neurological disorders, such as neurodegenerative diseases, viral and immunological encephalitides, and epilepsy. Both experimental and clinical evidence suggests a different inflammatory response to seizures in patients with temporal lobe epilepsy (TLE) in comparison to those with extra-TLE (XTLE). Proinflammatory cytokines and several autoantibodies have been shown to be associated with TLE compared to other epilepsy types suggesting the specific role and structure of the temporal lobe. Abundant experience suggests that activation of both innate and adaptive immunity is associated with epilepsy, particularly refractory focal epilepsy. Limbic encephalitis often triggers temporal lobe seizures, and a proportion of these disorders are immune-mediated. Histological evidence shows activation of specific inflammatory pathways in resected temporal lobes of epileptic patients, and certain epileptic disorders have shown increased incidence in patients with autoimmune diseases. Rapid activation of proinflammatory cytokines is observed after single seizures, but there is also evidence of chronic overproduction of cytokines and other inflammatory mediators in patients with TLE, suggesting a neuromodulatory role of inflammation in epilepsy. In this review we summarize current data on the presence and the role of immunological factors in temporal lobe seizures, and their possible involvement in epileptogenesis.

C-reactive protein and seizures in focal epilepsy: a video-electroencephalographic study.

PURPOSE: C-reactive protein (CRP) has been studied extensively in many noninflammatory neurologic conditions, but there has been little study of CRP in the context of seizures or epilepsy. The purpose of this study was to examine CRP concentrations in patients with refractory focal epilepsy who were undergoing video-electroencephalography (EEG) monitoring compared with healthy controls, and CRP change during 24 h after a seizure. METHODS: CRP levels were measured in serum at the onset of video-EEG recording (CRP-0h) and at 3, 6, 12, and 24 h after index seizure (the first verified localized-onset seizure) in 31 patients during inpatient video-EEG monitoring by using high sensitivity measurement of CRP concentration. The patients were categorized into two groups: temporal lobe epilepsy (TLE; n = 15) and extratemporal lobe epilepsy (XLE; n = 16). Eighty healthy volunteers served as controls. KEY FINDINGS: CRP-0h concentration was significantly higher in patients with refractory focal epilepsy than in controls (3.5 vs. 0.7 mg/ml, p < 0.001). All five patients with elevated CRP-0h (>mean + 2 standard deviations in controls) had TLE (vs. none in XLE; p = 0.018). Index seizure type was associated with CRP increase from baseline to maximum level after index seizure (p = 0.005). The most important predictor of increase in CRP level was secondarily generalized tonic-clonic seizure (SGTCS; p = 0.030). SIGNIFICANCE: The higher baseline levels in patients with epilepsy compared with healthy controls demonstrates that CRP concentrations are also affected in refractory epilepsy. Our data suggest that SGTCS stimulates CRP production. These results emphasize the association between inflammation and refractory epilepsy.

Elevated serum neuron-specific enolase in patients with temporal lobe epilepsy: a video-EEG study.

Established markers of brain damage, neuron-specific enolase (NSE) and S-100b protein (S-100), may increase after status epilepticus, but whether a single tonic-clonic or complex partial seizure induces elevation of these markers is not known. Furthermore, it is unclear whether the risk of seizure-related neuronal damage in temporal lobe epilepsy (TLE) differs from that in extratemporal lobe epilepsies (XTLE). The aim of this study was to analyze NSE and S-100 in patients with TLE and XTLE after acute seizures. The levels of NSE and S-100 were measured in serum before (0h) and at 3, 6, 12, and 24h after acute seizures in 31 patients during inpatient video-EEG monitoring. The patients were categorized into the TLE and the XTLE group based on video-EEG recordings and MRI findings. Fifteen patients had TLE and 16 XTLE. Index seizures were mainly complex partial seizures (n=21). In TLE mean+/-S.D. values for NSE levels (mug/L) were 8.36+/-2.64 (0h), 11.35+/-3.84 (3h), 13.48+/-4.49 (6h), 12.95+/-5.46 (12h) and 10.33+/-3.13 (24h) (p=0.006, ANOVA). In XTLE the changes were not significant (p=0.3). There was less increase in the levels of S-100 in TLE (p=0.05) and no significant change in XTLE (p=0.4). The levels of markers of neuronal damage were increased in patients with TLE, not only after tonic-clonic but also after complex partial seizures. These data suggest that TLE may be associated with brain damage.