Efficacy of perampanel: a review of clinical trial data.

The efficacy of adjunctive perampanel has been investigated in an extensive clinical development program across a broad, multinational population of patients with refractory partial-onset seizures. Further to the results of two Phase II dose-finding studies, perampanel was evaluated in three large Phase III registration studies at the predicted no-effect dose of 2 mg/day and the predicted effective doses of 4, 8, and 12 mg/day. In all three studies, perampanel 4, 8, and 12 mg/day consistently provided significant reductions in the frequency of partial-onset seizures compared with placebo. Improvements in responder rates and seizure freedom rates were also observed. In addition, data from recent interim analyses of extension studies have indicated that these efficacy outcomes may be maintained with long-term treatment. Overall, these studies form a solid evidence base to support the efficacy of adjunctive perampanel in the treatment of refractory partial-onset seizures.

Safety and tolerability of perampanel: a review of clinical trial data.

The Phase II and Phase III clinical development program of perampanel is providing a wealth of data on the safety and tolerability of this alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonist as an adjuvant treatment for refractory partial-onset seizures. In Phase II dose-finding studies, perampanel was associated with an acceptable tolerability profile up to the maximum evaluated dose of 12 mg/day. Subsequent multinational, multicenter, randomized, double-blind, placebo-controlled Phase III registration studies further supported the tolerability of perampanel across the dose range 2-12 mg/day, with interim data from ongoing extension studies indicating that safety outcomes may be maintained over several years. An analysis of the pooled Phase III data indicated that the frequency of adverse events reported with perampanel generally increased in a dose-dependent manner, and the most common adverse events were dizziness and somnolence. Overall, perampanel has been associated with an acceptable and consistent safety profile that is maintained over long-term settings.

Multimodality approach in cryptogenic epilepsy with focus on morphometric 3T MRI.

PURPOSE: This study aimed to investigate the potential contribution of morphometric MRI analysis in comparison to other modalities, such as MEG, SPECT and PET, in identifying the epileptogenic focus in patients with cryptogenic epilepsy. PATIENTS AND METHODS: Study inclusion was limited to epilepsy patients with a monolobar focus hypothesis, as concluded from EEG/seizure semiology and the best individual concordance rate. Feature maps, generated by the MATLAB(®) "morphometric analysis program" (MAP), were evaluated by a neuroradiologist blinded to conventional MRI and the focus hypothesis (MAP(1)). In addition, the feature maps were also interpreted by simultaneous matching conventional MRI but, again, with the reader having no knowledge of the focus hypothesis (MAP(2)). RESULTS: In 12 out of 51 patients, true-positive findings were achieved (MAP(1): sensitivity 24%; specificity 96%). The sensitivity of the MAP(1) results was superior extratemporally. After matching conventional MRI, FCD was traced in six of the 12 patients (MAP(2): sensitivity 12%; specificity 100%). MEG sensitivity was 62%. Sensitivity of interictal and ictal SPECT was 20% and 50%, respectively. PET was not as sensitive extratemporally (19%) as temporally (82%). The greatest correspondence with the best individual concordance rate was noted with PET (14/16; 88%) and MEG (8/10; 80%), followed by interictal (5/8; 63%) and ictal (9/15; 60%) SPECT. Results for MAP(1) were 53% (10/19), and 100% for MAP(2) (6/6). CONCLUSION: Although MAP sensitivity and specificity results are lower in comparison to other modalities, implementation of the technique should be considered first, before arranging any further investigations. The present study results offer guidelines for the implementation, interpretation and concordance of diagnostic procedures.

Multi-voxel magnetic resonance spectroscopy at 3 T in patients with idiopathic generalised epilepsy.

PURPOSE: The objective of our study was to gain further insight into the extent of local metabolic alterations in patients with idiopathic generalised epilepsy (IGE), respectively, the subgroup with generalised tonic-clonic seizures (GTCS). The extent of regional metabolic involvement perhaps indicates the key structures in generation of seizures and involvement of specific network of dysfunction. METHODS: Using the multi-voxel technique at a 3 T MRI Scanner metabolite levels of 25 age-matched healthy controls and 18 patients with GTCS were obtained from the basal ganglia, insular cortex, cingulum, hippocampus and along both hemispheres in the fronto-parietal white and grey matter. RESULTS: Group analysis of GTCS patients versus healthy controls revealed significant (p < 0.05) decrease of tNAA in the cortex of the central region and cingulum, but also in the thalami. Glx was elevated broadly in both hemispheres, in particular in central region, cingulum, insular cortex and left putamen, yet also in the right thalamus. Cho and mI demonstrated a significant coincidental decrease pronounced in the grey and white matter of the central region. Significant metabolic correlation (p ≤ 0.05) based on tNAA, respectively, Glx occurred between the thalamus and the central region, cingulum, putamen and medial frontal cortex. In patients with > 2 tonic-clonic seizures in the last 12 months a trend towards higher Glx and lower tNAA levels was observed. DISCUSSION: Our results demonstrate the altered metabolic interconnection of cerebral anatomic regions in patients with GTCS, in particular the major role of basal ganglia-central region relay in seizure generation.

Phenomenology of hallucinations, illusions, and delusions as part of seizure semiology.

In partial epilepsy, a localized hypersynchronous neuronal discharge evolving into a partial seizure affecting a particular cortical region or cerebral subsystem can give rise to subjective symptoms, which are perceived by the affected person only, that is, ictal hallucinations, illusions, or delusions. When forming the beginning of a symptom sequence leading to impairment of consciousness and/or a classic generalized seizure, these phenomena are referred to as an epileptic aura, but they also occur in isolation. They often manifest in the fully awake state, as part of simple partial seizures, but they also can be associated to different degrees of disturbed consciousness. Initial ictal symptoms often are closely related to the physiological functions of the cortical circuit involved and, therefore, can provide localizing information. When brain regions related to sensory integration are involved, the seizure discharge can cause specific kinds of hallucinations, for example, visual, auditory, gustatory, olfactory, and cutaneous sensory sensations. In addition to these elementary sensory perceptions, quite complex hallucinations related to a partial seizure can arise, for example, perception of visual scenes or hearing music. By involving psychic and emotional spheres of human perception, many seizures also give rise to hallucinatory emotional states (e.g., fear or happiness) or even more complex hallucinations (e.g., visuospatial phenomena), illusions (e.g., déjà vu, out-of-body experience), or delusional beliefs (e.g., identity change) that often are not easily recognized as epileptic. Here we suggest a classification into elementary sensory, complex sensory, and complex integratory seizure symptoms. Epileptic hallucinations, illusions, and delusions shine interesting light on the physiology and functional anatomy of brain regions involved and their functions in the human being. This article, in which 10 cases are described, introduces the fascinating phenomenology of subjective seizure symptoms.

Ictal delusion of sexual transformation.

Psychic and psychotic symptoms can be part of seizure-related symptoms, especially within the postictal phase in partial epilepsies. Among the classic examples are dysmnestic phenomena, visual and acoustic hallucinations, and more rarely delusional syndromes. Here we report about the unique seizure symptom of transformation towards the opposite gender in a patient with a right amygdalar tumor, which we classify as ictal delusional misidentification syndrome.

Clinical prediction of postoperative seizure control: structural, functional findings and disease histories.

OBJECTIVE: Mesial temporal lobe epilepsy (MTLE) constitutes a heterogenic entity with different clinical histories, pathomorphological hippocampal findings and varying postoperative outcome. METHOD: 64 patients with MTLE, scheduled for hippocampal resection, were included. Initial precipitating injuries (IPI), structural and functional findings and neuropathological classification of hippocampal specimens were related to prediction of surgical outcome. RESULTS: Patients with severe hippocampal sclerosis (mesial temporal sclerosis (MTS) type 1b) became completely seizure free (80% Engel Ia) significantly more often compared with approximately 40% of seizure freedom in other types of MTS or in patients without hippocampal cell loss (non-MTS), irrespective of the extent of hippocampal resection. Age at IPI was found to be related to MTS variants (p<0.01) and significantly correlated with cell loss in the CA1 sector and the dentate gyrus (p<0.05). Presurgical MRI discriminated between MTS and non-MTS, but did not discriminate between different MTS subtypes. The most reliable predictors of MTS type 1b were the Wada memory scores combined with interictal and ictal EEG. CONCLUSIONS: A particular cohort of MTLE patients benefit most from surgical treatment. These patients are clinically best recognised as presenting with (1) very early IPI; (2) a silent period of about 5 years; (3) unequivocal unilateral EEG localisation; (4) MRI signs of MTS; and (5) Wada Test indicates contralateral memory compensation and ipsilateral reduced memory capacity. MTS type 1b, characterised by severe cell loss in all hippocampal subfields including the dentate gyrus, and associated with optimal postoperative seizure control, was preoperatively clinically best differentiated from other MTS types by the Wada Memory Test.

Magnetic resonance spectroscopy and histopathological findings in temporal lobe epilepsy.

PURPOSE: In some patients with temporal lobe epilepsy, histopathological evaluation of resected brain tissue after surgical treatment may reveal several features indicative of discrete cortical malformations. We sought to determine whether these histopathological features were accompanied by hippocampal changes detectable preoperatively by proton magnetic resonance (MR) spectroscopy and to evaluate their relationship with postoperative outcome. METHODS: In 25 consecutive temporal lobe epilepsy patients who were scheduled for surgical treatment, MR spectroscopy was performed, and resected brain tissue was analyzed histopathologically for the presence of discrete cortical malformations (e.g., microdysgenesis). Outcome was assessed in all patients with an average postoperative period of 26 months. RESULTS: In 13 patients, we found subtle, histopathologically detectable signs of cortical malformation: 6 of them with concomitant hippocampal sclerosis (dual pathology) and 7 without. The latter subgroup had a worse surgical outcome and showed enhanced bilateral and/or contralateral pathological changes in the hippocampal formation when investigated by MR spectroscopy. CONCLUSIONS: These data suggest that by showing contralaterally or bilaterally abnormal spectra, MR spectroscopy might be able to indicate pathological changes in subtle developmental disorders that are possibly more widespread over the brain. This observation may improve noninvasive diagnosis in presurgical evaluation and the neurobiological understanding of cortical malformations in pharmacoresistant temporal lobe epilepsy.

Temporal lobe microdysgenesis in epilepsy versus control brains.

Histopathologic evaluation of brain tissue derived from surgically treated patients with medically refractory temporal lobe epilepsy (TLE) frequently reveals structural brain lesions in the surgical specimen. While several of the most commonly encountered lesions such as low-grade neoplasms or vascular malformations are well established as structural substrates of epilepsy, the significance of subtle microscopic characteristics has remained controversial. Within the spectrum a broad range of microscopic features has previously been reported as "mild cortical dysplasia," "focal cortical dysplasia," or "microdysgenesis," including cortical laminar disorganization, columnar arrangement of cortical neurons, marked clustering of neurons throughout cortical layers II-VI, increased numbers of molecular layer neurons, marked perivascular clustering of oligodendroglia in the white matter, single heterotopic neurons in the deep white matter, glioneuronal hamartia, giant neurons, and balloon cell change. In this paper we report the frequency of these features in temporal lobe tissue of 47 surgically treated TLE-patients vs 29 normal autopsy controls. While most of them were found in both cases and controls, clustering of neurons throughout cortical layers II-VI, perivascular clustering of oligodendroglia in the white matter, increased single heterotopic white matter neurons, and glioneuronal hamartias predominated in tissue from patients with epilepsy (p < 0.05). A count of more than 10 white matter neurons/HPF was associated with a worse postoperative outcome (p < 0.05). These data suggest that certain microscopic characteristics are associated with the epileptic process, while others appear as normal variants.