Antibodies Contributing to Focal Epilepsy Signs and Symptoms Score.

OBJECTIVE: Diagnosing autoimmune encephalitis (AIE) is difficult in patients with less fulminant diseases such as epilepsy. However, recognition is important, as patients require immunotherapy. This study aims to identify antibodies in patients with focal epilepsy of unknown etiology, and to create a score to preselect patients requiring testing. METHODS: In this prospective, multicenter cohort study, adults with focal epilepsy of unknown etiology, without recognized AIE, were included, between December 2014 and December 2017, and followed for 1 year. Serum, and if available cerebrospinal fluid, were analyzed using different laboratory techniques. The ACES score was created using factors favoring an autoimmune etiology of seizures (AES), as determined by multivariate logistic regression. The model was externally validated and evaluated using the Concordance (C) statistic. RESULTS: We included 582 patients, with median epilepsy duration of 8 years (interquartile range = 2-18). Twenty patients (3.4%) had AES, of whom 3 had anti-leucine-rich glioma inactivated 1, 3 had anti-contactin-associated protein-like 2, 1 had anti-N-methyl-D-aspartate receptor, and 13 had anti-glutamic acid decarboxylase 65 (enzyme-linked immunosorbent assay concentrations >10,000IU/ml). Risk factors for AES were temporal magnetic resonance imaging hyperintensities (odds ratio [OR] = 255.3, 95% confidence interval [CI] = 19.6-3332.2, p < 0.0001), autoimmune diseases (OR = 13.31, 95% CI = 3.1-56.6, p = 0.0005), behavioral changes (OR 12.3, 95% CI = 3.2-49.9, p = 0.0003), autonomic symptoms (OR = 13.3, 95% CI = 3.1-56.6, p = 0.0005), cognitive symptoms (OR = 30.6, 95% CI = 2.4-382.7, p = 0.009), and speech problems (OR = 9.6, 95% CI = 2.0-46.7, p = 0.005). The internally validated C statistic was 0.95, and 0.92 in the validation cohort (n = 128). Assigning each factor 1 point, an antibodies contributing to focal epilepsy signs and symptoms (ACES) score ≥ 2 had a sensitivity of 100% to detect AES, and a specificity of 84.9%. INTERPRETATION: Specific signs point toward AES in focal epilepsy of unknown etiology. The ACES score (cutoff ≥ 2) is useful to select patients requiring antibody testing. ANN NEUROL 2021;89:698-710.

A prospective study on changes in blood levels of cholecystokinin-8 and leptin in patients with refractory epilepsy treated with the ketogenic diet.

OBJECTIVE: To evaluate the changes in serum CCK-8 and leptin levels in patients with refractory epilepsy treated with the ketogenic diet (KD). METHODS: In this prospective study, patients aged between one and 40 years with refractory epilepsy were included. CCK-8 and leptin were measured in serum at baseline and after three and 12 months of treatment with the KD using an enzyme-linked Immunoabsorbant Assay. Seizure frequency and responsiveness were calculated. RESULTS: Fifty-four patients were included; 26 patients (48%) were still on the KD at 12 months. After three and 12 months, respectively, 39% and 26% were responders. CCK-8 values were statistically significantly increased at three months (p=0.005) and 12 months (p=0.012). In responders, at three months follow-up, this increase of CCK-8 was significant (p=0.020), whereas in the non-responders it was not (p=0.34). Leptin values were decreased at three and 12 months, the decrease at three months being statistically significant in post-pubertal men (p=0.028) and post-pubertal women (p=0.007). SIGNIFICANCE: In responders to the KD, serum CCK-8 increased statistically significantly during treatment at three months. Serum leptin decreased statistically significantly at three months in men and in post-pubertal women. It is plausible that the increase of CCK-8 and the decrease of leptin contribute to the anti-convulsive effect of the KD.

The MCT-ketogenic diet as a treatment option in refractory childhood epilepsy: A prospective study with 2-year follow-up.

The present study assessed the long-term (i.e., 24months) efficacy of the ketogenic diet (KD) as an add-on therapy in children with refractory epilepsy, with focus on seizure frequency, seizure severity, and tolerability. Most patients were treated with the MCT-diet. At one and two years, 33% and 23%, respectively, of the 48 included patients were still on the KD. After three months, one year, and two years of treatment, 16.7% of the patients were responders. The highest responder rate (i.e., 22.9%) was seen at six and nine months of treatment. Of the fifteen patients with seizure clusters during baseline, 60% were responders after three months when looking at cluster reduction and most of them were not responders for the total seizure frequency. From three months of treatment onwards, most of the patients had a relevant decrease in seizure severity which was mainly related to the most severe seizure type. Gastrointestinal dysfunction was often reported, especially in the first six weeks of treatment. Growth deceleration was present in 30% of the patients, and weight reduction in 15%. Improved arousal was mentioned in 30% of patients. No patients developed ECG abnormalities or kidney stones. Increase in lipid profile was rare. The KD is an effective therapy for children with therapy-resistant epilepsy. Effectiveness is reflected in the reduction of seizure frequency as well as in the reduction of seizure severity. After 6months of treatment, it is obvious which patients are responders and tolerate the treatment well. Most of these patients will continue to benefit from the KD for a longer time. Long-term use of the diet was well tolerated.

Can an early 24-hour EEG predict the response to the ketogenic diet? A prospective study in 34 children and adults with refractory epilepsy treated with the ketogenic diet.

PURPOSE: We examined whether early EEG changes in a 24-h EEG at 6 weeks of treatment were related to the later clinical response to the ketogenic diet (KD) in a 6-month period of treatment. METHODS: We examined 34 patients with heterogeneous epilepsy syndromes (21 children, 13 adults) and found 9 clinical responders (≥50% seizure reduction); this is a responder rate of 26%. We visually counted the interictal epileptic discharge index (IED index) in % during 2h of wakefulness and in the first hour of sleep (method 1), and also globally reviewed EEG changes (method 2), while blinded to the effect of the KD. RESULTS: At group level we saw a correlation between nocturnal reduction of IED-index at 6 weeks and seizure reduction in the follow-up period. A proportional reduction in IED index of 30% from baseline in the sleep EEG, was associated with being a responder to the diet (Pearson Chi-square p=0.04). EEG scoring method 2 observed a significantly larger proportion of patients with EEG-improvement in sleep in KD responders than in non-responders (p=0.03). At individual level, however, EEG changes did not correlate very strongly to the response to the diet, as IED reduction in sleep was also seen in 15% (method 1) to 26% (method 2) of the non-responders. CONCLUSION: Nocturnal reduction of IEDs is related to the response to the KD, however in daily clinical practice, an early EEG to predict seizure reduction should not be advised for individual patients.

The ketogenic diet as a treatment option in adults with chronic refractory epilepsy: efficacy and tolerability in clinical practice.

The ketogenic diet (KD) is a high-fat, low-protein, low-carbohydrate diet that is used as a treatment for patients with difficult-to-control epilepsy. The present study assesses the efficacy and tolerability of the KD as an add-on therapy in adults with chronic refractory epilepsy. 15 adults were treated with the classical diet or MCT diet. During a follow-up period of 1 year we assessed seizure frequency, seizure severity, tolerability, cognitive performance, mood and quality of life (QOL). We found a significant reduction in seizures among the patients who followed the diet at least 1 year (n=5). Of these 5 patients, 2 had a reduction between 50 and 90%. Analyzing the study months separately, we found a seizure reduction of ≥50% in 26.6% of the patients during at least 1 month of treatment. Common side-effects were gastrointestinal disorders, loss of weight and fatigue. There was a considerable, non-significant improvement found in mood and QOL scores. Improvements were independent of reduction in seizure frequency, indicating that the effects of the KD reach further than seizure control.