There is scant evidence to guide the management of infantile spasms after successful response to initial therapies. There is significant risk of relapse, largely because effective pharmacologic treatments cannot be continued long term because of concern for significant adverse events. Zonisamide (ZNS) and topiramate (TPM) are commonly used to prevent relapse, and the purpose of this study was to specifically evaluate the efficacy of ZNS and TPM as agents for secondary prevention of infantile spasms.Methods
Patients with video–electroencephalography (EEG) confirmed resolution of infantile spasms were retrospectively identified. Relevant clinical data were systematically collected, including lead time from onset of spasms to successful treatment response, etiology of infantile spasms, number of treatment failures prior to response, timing of relapse, and detailed exposure data for ZNS and TPM.Results
We identified 106 patients with response to hormonal therapy (n = 58), vigabatrin (n = 25), or surgery (n = 23). To prevent relapse of infantile spasms, 37 patients received ZNS, 34 received TPM, 3 received both ZNS and TPM, and 38 patients received neither ZNS nor TPM. There were 44 relapses, occurring a median of 6.9 (3.2–10.8) months after initial response. Time to relapse was not affected by treatment with ZNS or TPM. Relapse was less likely among patients who were older (hazard ratio 0.97 [per month], p = 0.036) and those who responded to surgical resection (hazard ratio = 0.28, p = 0.017). Of note, we identified a relatively refractory cohort with multiple treatment failures and long lead time to initial response.Significance
In this refractory cohort, neither ZNS nor TPM was successful in preventing relapse of infantile spasms, despite relatively high dosages. At this time, aside from surgical resection in eligible candidates, there is no known treatment that is efficacious in the prevention of relapse of infantile spasms.
The aim of our study was to investigate the neuronal networks underlying background oscillations of epileptic encephalopathy with continuous spikes and waves during slow sleep (CSWS).Methods
Sleep electroencephalography (EEG) studies before and after the treatment were investigated in 15 patients with CSWS. To investigate functional and effective connectivity within the network generating the delta activity in the background sleep EEG, the methods of dynamic imaging of coherent sources (DICS) and renormalized partial directed coherence (RPDC) were applied.Results
Independent of etiology and severity of epilepsy, background EEG pattern in patients with CSWS before treatment is associated with the complex network of coherent sources in medial prefrontal cortex, somatosensory association cortex/posterior cingulate cortex, medial prefrontal cortex, middle temporal gyrus/parahippocampal gyrus/insular cortex, thalamus, and cerebellum. The analysis of information flow within this network revealed that the medial parietal cortex, the precuneus, and the thalamus act as central hubs, driving the information flow to other areas, especially to the temporal and frontal cortex. The described CSWS-specific pattern was no longer observed in patients with normalized sleep EEG. In addition, frequency of spiking showed a strong linear correlations with absolute source power, source coherence strength, and source RPDC strength at both time points: (1) Spike and wave index (SWI) versus absolute source power at EEG1 (r = 0.56; p = 0.008) and at EEG2 (r = 0.45; p = 0.009); (2) SWI versus source coherence strength at EEG1 (r = 0.71; p = 0.005) and at EEG2 (r = 0.52; p = 0.006); and (3) SWI versus source RPDC strength at EEG1 (r = 0.65; p = 0.003) and at EEG2 (r = 0.47; p = 0.009).Significance
The leading role of the precuneus and thalamus in the hierarchical organization of the network underlying the background EEG points toward the significance of fluctuations of vigilance in the generation of CSWS. This hierarchical network organization appears to be specific for CSWS as it is resolved after successful treatment.
5-Hydroxytryptophan, a precursor for serotonin synthesis, reduces seizure-induced respiratory arrest
The DBA/1 mouse is a relevant animal model of sudden unexpected death in epilepsy (SUDEP), as it exhibits seizure-induced respiratory arrest (S-IRA) evoked by acoustic stimulation, followed by cardiac arrhythmia and death. Defects in serotonergic neurotransmission may contribute to S-IRA. The tryptophan hydroxylase-2 (TPH2) enzyme converts L-tryptophan to 5-hydroxytryptophan (5-HTP), a precursor for central nervous system (CNS) serotonin (5-HT) synthesis; and DBA/1 mice have a polymorphism that decreases TPH2 activity. We, therefore, hypothesized that supplementation with 5-HTP may bypass TPH2 and suppress S-IRA in DBA/1 mice.Methods
TPH2 expression was examined by Western blot in the brainstem of DBA/1 and C57BL/6J mice both with and without acoustic stimulation. Changes in breathing and cardiac electrical activity in DBA/1 and C57BL/6J mice that incurred sudden death during generalized seizures evoked by pentylenetetrazole (PTZ) were studied by plethysmography and electrocardiography. The effect of 5-HTP administration on seizure-induced mortality evoked by acoustic stimulation or by PTZ was investigated in DBA/1 mice.Results
Repetitive acoustic stimulation resulted in reduced TPH2 protein in the brainstem of DBA/1 mice as compared with C57BL/6J mice. S-IRA evoked by acoustic stimulation in DBA/1 mice was significantly reduced by 5-HTP. Following S-IRA, cardiac electrical activity could be detected for minutes before terminal asystole and death in both DBA/1 and C57BL/6J mice after PTZ treatment. The incidence of S-IRA by PTZ administration was greater in DBA/1 than in C57BL/6J mice, and administration of 5-HTP also significantly reduced S-IRA by PTZ in DBA/1 mice.Significance
Our data suggest that S-IRA is the primary event leading to death incurred in most DBA/1 and some C57BL/6J mice during PTZ-evoked seizures. Suppression of S-IRA by 5-HTP suggests that 5-HT transmission contributes to the pathophysiology of S-IRA, and that 5-HTP, an over-the-counter supplement available for human consumption, may be clinically useful in preventing SUDEP.
Leucine-rich glioma inactived-1 (LGI1) antibodies are associated with limbic encephalitis and distinctive seizure types, which are typically immunotherapy-responsive. Although nonspecific electroencephalography (EEG) abnormalities are commonly seen, specific EEG characteristics are not currently understood to be useful for suspecting the clinical diagnosis. Based on initial observations in two patients, we analyzed the clinical features and EEG recordings in a larger series of patients (n = 9) and describe a novel ictal pattern that can suggest the diagnosis of LGI1-antibody–mediated encephalitis, even in the absence of typical clinical features. As expected, psychiatric and cognitive symptoms were common, as were tonic seizures associated with EEG electrodecremental events (often with the so-called faciobrachial dystonic semiology). Remarkably, in five patients, a near absence of interictal epileptiform discharges contrasted with frequent subclinical temporal lobe seizures, at times triggered by hyperventilation. This latter EEG pattern may facilitate early diagnosis of this serious but potentially treatable condition.
Atrophy of the pedunculopontine nucleus region in patients with sleep-predominant seizures: A voxel-based morphometry study
Non–rapid eye movement (NREM) sleep increases interictal epileptiform discharges and frequency of seizures, whereas REM sleep suppresses them. The pedunculopontine nucleus (PPN), one of the REM sleep–modulating structures, is postulated to have a potent antiepileptogenic role. We asked if patients with sleep-predominant seizures (SPS) show volume changes in the region of the PPN compared to those with seizures occurring during awake state only (nSPS). The volume of the PPN region was assessed in patients with SPS, those with nSPS, and healthy volunteers, through voxel-based morphometry and automated, nonbiased region of interest (ROI) analysis of T1 magnetic resonance (MR) images. The volume of PPN region was statistically smaller in patients with SPS (n = 33) than in those with nSPS (n = 40) and healthy controls (n = 30) after controlling for covariates. These results suggest that a structural change in the PPN may be associated with sleep-predominant timing of seizure occurrence. Our findings might help understand the intervening pathomechanism that lies between the human sleep–wake cycle and epilepsy.
Seizure-onset zone localization by statistical parametric mapping in visually normal 18F-FDG PET studies
Neuroimaging is crucial in the presurgical evaluation of patients with medically refractory epilepsy. To improve the moderate sensitivity of [18F]fluorodeoxyglucose–positron emission tomography (18F-FDG-PET), our aim was to evaluate the usefulness of statistical parametric mapping (SPM) to localize the seizure-onset zone (SOZ) in PET studies deemed normal by visual assessment.Methods
Fifty-five patients with medically refractory epilepsy whose 18F-FDG-PET was visually evaluated as normal were retrospectively included. Twenty of these patients had undergone surgical intervention. PET images were analyzed by SPM8 using a corrected p-value of p < 0.05 and three uncorrected p-values of p < 0.0001, p < 0.001, and p < 0.005, matched with minimum cluster sizes of k > 0, k > 20, k > 100, and k > 200, respectively. The SPM-identified potential seizure zone (SZ) was compared to the SOZ, which was determined by consensus during patient management meetings in the epilepsy unit, taking into account presurgical tests. Studies in which the SPM-identified potential SZ was concordant with the SOZ were considered “correctly localizing.”Results
The SPM threshold combination with the least restrictive p-value and greatest minimum cluster size achieved the highest rate of correctly localizing studies. When p < 0.005/k > 200 was used, 40% (22/55) of studies were correctly localizing, and the concordance obtained in the surgically intervened subgroup was substantial (к = 0.607, 95% confidence interval [CI] 0.258–0.957), which was comparable to the concordance obtained by magnetic resonance imaging (MRI) (к = 0.783, 95% CI 0.509–1.000).Significance
SPM offers improved SOZ localization in 18F-FDG-PET studies that are negative on visual assessment. For this purpose, statistical parametric maps could be thresholded with liberal p-values and restrictive cluster sizes.