Epilepsy with eyelid myoclonia (Jeavons syndrome): Generalized, focal, or combined generalized and focal epilepsy syndrome?

Epilepsy with eyelid myoclonia (EM) or Jeavons syndrome (JS) is an epileptic syndrome related to the spectrum of genetic generalized epilepsies (GGE). We report two untreated children on which EEGs were performed several hours after a generalized tonic-clonic seizure (GTCS). These showed a unilateral, nearly continuous posterior slowing. This slow-wave activity was associated with contralateral epileptiform activity in one case, while in the second case, it was associated with an ipsilateral activity. However, in the latter child, a few months later an independent focus on the contralateral side was observed. A diagnosis of focal occipital lobe epilepsy was proposed in both cases, and one child underwent a left occipital lobectomy at 3.5 years of age. Despite surgery, absences with EM persisted in this child, and a marked photosensitivity to photic stimulation was observed two years later. The focal slow wave activity of one occipital lobe several hours after a GTCS in these two subjects was in favor of a focal onset preceding the generalization. The EEG evidence for independent left and right posterior focus in these two cases, the persistence of EM, and the development of a marked photosensitivity to photic stimulation in the child who underwent an occipital lobectomy, allow us to suggest that JS is associated with a network of bi-occipital hyperexcitability that rapidly engages bilaterally to produce generalized seizures.

Perampanel in 12 patients with Unverricht-Lundborg disease.

OBJECTIVE: Perampanel (PER) was used in 12 patients with Unverricht-Lundborg disease (ULD) to evaluate its efficacy against myoclonus and seizures. METHODS: We treated 11 patients with EPM1 mutations (6 F, 5 M, aged 13-62 years) and a 43-year-old man with de novo KCNC1 mutation. PER was introduced by 2 mg steps at 2-4 week intervals until 6 mg/day, with a possible dose reduction or dose increase. RESULTS: Ten patients had a clear clinical response of myoclonus, and five were able to reduce concomitant therapy. Improvement was noted sometimes as soon as with 2 mg/day. Epileptic seizures stopped on PER in the six patients who still had experienced generalized tonic-clonic or myoclonic seizures (100%). Some abatement of efficacy on myoclonus was seen in two patients who still retained some benefit. Weight gain was reported in six patients (50%). Psychological and behavioral side-effects were observed in six patients (50%) and led to withdrawal of PER in three cases and dose reduction in three, with abatement of the problems. SIGNIFICANCE: This study provides evidence that for ULD patients, PER may show marked efficacy even in severe cases, particularly against myoclonus, but also against seizures. PER should thus be tried in ULD patients whose seizures are not satisfactorily controlled. Its use is limited because of psychological and behavioral side effects, with higher doses of approximately 6 mg/day or greater likely risk factors.

Cost-effectiveness analysis of epilepsy surgery in a controlled cohort of adult patients with intractable partial epilepsy: A 5-year follow-up study.

OBJECTIVE: Despite its well-known effectiveness, the cost-effectiveness of epilepsy surgery has never been demonstrated in France. We compared cost-effectiveness between resective surgery and medical therapy in a controlled cohort of adult patients with partial intractable epilepsy. METHODS: A prospective cohort of adult patients with surgically remediable and medically intractable partial epilepsy was followed over 5 years in the 15 French centers. Effectiveness was defined as 1 year without a seizure, based on the International League Against Epilepsy (ILAE) classification. Clinical outcomes and direct costs were compared between surgical and medical groups. Long-term direct costs and effectiveness were extrapolated over the patients' lifetimes with a Monte-Carlo simulation using a Markov model, and an incremental cost-effectiveness ratio (ICER) was computed. Indirect costs were also evaluated. RESULTS: Among the 289 enrolled surgery candidates, 207 were operable-119 in the surgical group and 88 in the medical group-65 were not operable and not analyzed here, 7 were finally not eligible, and 10 were not followed. The proportion of patients completely seizure-free during the last 12 months (ILAE class 1) was 69.0% in the operated group and 12.3% in the medical group during the second year (p < 0.001), and it was respectively 76.8% and 21% during the fifth year (p < 0.001). Direct costs became significantly lower in the surgical group the third year after surgery, as a result of less antiepileptic drug use. The value of the discounted ICER was 10,406 (95% confidence interval [CI] 10,182-10,634) at 2 years and 2,630 (CI 95% 2,549-2,713) at 5 years. Surgery became cost-effective between 9 and 10 years after surgery, and even earlier if indirect costs were taken into account as well. SIGNIFICANCE: Our study suggests that in addition to being safe and effective, resective surgery of epilepsy is cost-effective in the medium term. It should therefore be considered earlier in the development of epilepsy.

Unverricht-Lundborg disease.

We first review the clinical presentation and current therapeutic approaches available for treating Unverricht-Lundborg disease (ULD), a progressive myoclonus epilepsy. Next, we describe the identification of disease causing mutations in the gene encoding cystatin B (CSTB). A Cstb-deficient mouse model, which recapitulates the key features of ULD including myoclonic seizures, ataxia, and neuronal loss, was generated to shed light on the mechanisms contributing to disease pathophysiology. Studies with this model have elucidated the diverse biological roles for Cstb from functioning as a protease inhibitor, to regulating glial activation, oxidative stress, serotonergic neurotransmission, and hyperexcitability. These findings set the stage for future studies that may open avenues to improved therapeutic approaches.

Mixed myoclonic-absence status epilepticus in juvenile myoclonic epilepsy.

Myoclonic status epilepticus or mixed absence-myoclonic status is uncommon in juvenile myoclonic epilepsy (JME), often precipitated by sleep deprivation, withdrawal of medication, or inadequate antiepileptic drugs (Thomas et al., 2006; Crespel et al., 2013). Such episodes respond well to benzodiazepines or valproate (Crespel et al., 2013). We present the video-EEG of a 24-year-old woman with JME and bipolar disorder. She had a confusional state five days after withdrawal of clonazepam (14 mg/d) and introduction of oxazepam (200 mg/d), followed by catatonic stupor with subtle myoclonus of the face and the arms. The EEG showed absence status (figures 1, 2), which stopped after IV injection of clonazepam (1 mg) (figure 3). Consciousness returned to normal [Published with video sequence and figures (1)].

Sleep before and after temporal lobe epilepsy surgery.

PURPOSE: Patients with epilepsy often complain of non-restorative sleep. This is the consequence of the acute effect of seizures and the chronic effect of epilepsy responsible for disrupting sleep architecture. Other factors such as antiepileptic drugs (AEDs), also play a role in the alteration of sleep organization. The aim of this study was to evaluate the specific effect of seizures and interictal epileptiform abnormalities (IEAs) on sleep, in particular to see whether reducing seizure frequency by epilepsy surgery might improve sleep organization in these patients. METHODS: Eleven patients with refractory mesial temporal lobe epilepsy, who underwent surgical treatment and who were seizure free at the follow-up, were included in the study. Treatment with AEDs was not significantly modified before the second year of follow-up. Patients were evaluated before surgery, at 1-year and 2-year follow-up visits with a videoEEG monitoring (24h/24). At each follow-up visit, interictal epileptiform abnormalities and sleep macrostructure parameters were assessed. RESULTS: All patients showed a reduction of their IEAs. At 1-year follow-up, total sleep time and REM sleep increased significantly (p=0.032 and p=0.006, respectively). At 2-year follow-up, an important increase of REM sleep was observed (p=0.028). Most significant variations were noted 1 year after surgery. No significant variations were observed between the first and the second year after surgery. CONCLUSIONS: Surgical treatment of temporal lobe epilepsy may improve sleep macrostructure by reducing the number of seizures and of IEAs. These results indirectly confirm the role of epilepsy in disrupting sleep organization chronically.

Parasagittal transinsular electrodes for stereo-EEG in temporal and insular lobe epilepsies.

OBJECTIVE: Direct invasive EEG recordings of the insula - due to its particular anatomical position, deeply seated between both opercula - can only be performed with intracerebral electrodes. To date, the technique most commonly used for insular stereoelectroencephalography (SEEG) is the orthogonal-transopercular electrode approach with the Talairach methodology. We propose another technique utilizing MRI with transinsular parasagittal electrodes and a posterior entry point. This avoids passing through the opercula and sylvian vessels running over the insular surface. METHODS: Nine patients, whose seizures implicated the insula, underwent brain surgery. Under general anesthesia with a Leksell frame, 3D-T(1) SPGR MRI with gadolinium enhancement was achieved. Surgical planning was performed using the StealthStation with an entry point in the parieto-occipital junction setting the target for the first contact of the lead at the most anterior part of the insula. The trajectory was manipulated in order to have at least 4 contacts per electrode track within the insular cortex. All patients had a postoperative MRI to verify the exact position of each contact. RESULTS: Insular seizures were recorded in all patients. There was neither intracranial bleeding nor infection. In all of the cases, except 1, the seizures recorded were found to be propagations of the primary epileptic zone located in the temporal lobe, either in the mesial structures or the superior temporal gyrus. Eight patients were operated, 7 with an antero-mesial temporal lobectomy and 1 with dysplasia of the superior temporal gyrus. No insular resections were performed. CONCLUSION: We report a novel technique for insular SEEG with parasagittal electrodes, parallel to the insular cortex, with an entry point at the parieto-occipital junction. This technique is based entirely on use of MRI, and avoids passing through the opercula and sylvian vessels.

Discrepancies between preoperative stereoencephalography language stimulation mapping and intraoperative awake mapping during resection of focal cortical dysplasia in eloquent areas.

BACKGROUND/AIMS: To compare the reliability of preoperative stereoencephalography (SEEG) and intraoperative electrostimulation regarding functional mapping, and to select the indication for surgery for focal cortical dysplasia (FCD) in language areas. METHODS: The authors present the case of a 21-year-old, right-handed female, suffering from chronic pharmacologically resistant epilepsy since the age of 8. MRI showed a subcortical hypersignal on FLAIR and T(2) sequences at the posterior end of the left superior temporal sulcus compatible with an FCD. SEEG invasive monitoring was performed to precisely identify the epileptogenic zone (EZ) and for functional language mapping. RESULTS: The stimulation of the contacts implicated in the EZ through SEEG leads induced language disturbances, which were not reproducible. Surgery was performed under local anesthesia with awake corticosubcortical mapping. Direct intraoperative stimulation in the EZ, including FCD, did not induce language disturbances. Thus, EZ could be removed completely without any postoperative language deficit. CONCLUSIONS: The present case suggests that when language disturbances which occur during invasive SEEG functional mapping, in eloquent areas, are not reproducible, resection can be considered using intraoperative electrical mapping, without inducing permanent language impairment. This may be explained by a certain degree of plasticity and reshaping of functional areas associated with a congenital lesion and chronic epilepsy.

Comparison of carbamazepine and oxcarbazepine effects on aminothiol levels.

OBJECTIVE: The aim of our study was to investigate the effects of carbamazepine (CBZ) and oxcarbazepine (OXCBZ) on aminothiol levels, including homocysteine (Hcy), cysteine, and cysteinylglycine, in chronically treated patients. METHODS: Epileptic patients receiving CBZ or OXCBZ were recruited as part of routine clinical practice. Demographic data and concomitant medications were recorded from the patient medical file. RESULTS: Sixty patients were included in the study; 30 patients were treated with CBZ and 30 with OXCBZ. Median Hcy level was significantly higher in CBZ-treated patients (20.6 micromol/l) than in OXCBZ-treated patients (14.0 micromol/l, p < 0.0001). No correlation was evidenced between antiepileptic drugs or metabolite levels and Hcy levels for each group. CONCLUSIONS: Less change observed with OXCBZ compared with CBZ on aminothiol levels could constitute an advantage for OXCBZ treatment in patients with other factors influencing Hcy levels and/or at high risk for cardiovascular diseases.

Angiogenesis is associated with blood-brain barrier permeability in temporal lobe epilepsy.

Previous studies from our group, focusing on neuro-glial remodelling in human temporal lobe epilepsy (TLE), have shown the presence of immature vascular cells in various areas of the hippocampus. Here, we investigated angiogenic processes in hippocampi surgically removed from adult patients suffering from chronic intractable TLE, with various aetiologies. We compared hippocampi from TLE patients to hippocampi obtained after surgery or autopsy from non-epileptic patients (NE). We quantified the vascular density, checked for the expression of angiogenic factors and their receptors and looked for any blood-brain barrier (BBB) leakage. We used a relevant model of rat limbic epilepsy, induced by lithium-pilocarpine treatment, to understand the sequence of events. In humans, the vessel density was significantly higher in TLE than in NE patients. This was neither dependent on the aetiology nor on the degree of neuronal loss, but was positively correlated with seizure frequency. In the whole hippocampus, we observed many complex, tortuous microvessels. In the dentate gyrus, when the granular layer was dispersed, long microvessels appeared radially orientated. Vascular endothelial factor (VEGF) and tyrosine kinase receptors were detected in different types of cells. An impairment of the BBB was demonstrated by the loss of tight junctions and by Immunoglobulines G (IgG) leakage and accumulation in neurons. In the rat model of TLE, VEGF over-expression and BBB impairment occurred early after status epilepticus, followed by a progressive increase in vascularization. In humans and rodents, angiogenic processes and BBB disruption were still obvious in the chronic focus, probably activated by recurrent seizures. We suggest that the persistent leakage of serum IgG in the interstitial space and their uptake by neurons may participate in hypoperfusion and in neuronal dysfunction occurring in TLE.

Increased number of neural progenitors in human temporal lobe epilepsy.

An increased neurogenesis is reported in animal models of mesial temporal lobe epilepsy (MTLE) but the fate of newborn cells is unknown. Here, we attempted to demonstrate neurogenesis in adult epileptic tissue obtained after hippocampectomy. MTLE hippocampi showed increased expression of division markers and of Musashi-1, a marker of neural progenitors, compared to control hippocampi. Large quantities of Musashi-1+ cells were obvious in the subgranular layer and the subventricular zone, both known neurogenic areas, and in the fissura hippocampi. Musashi-1 was expressed by small cells that were mainly vimentin+ or nestin+, rarely Dcx+ or PSA-NCAM+ and negative for markers of mature neurons or astrocytes. Some of them are present in the granular layer, the hilus, and CA1 area resembling the ectopic positions described in rodents. These findings demonstrate that neural progenitors proliferate in chronic epilepsy and suggest that the fissura hippocampi behaves like another neurogenic area.

Haplotype study of West European and North African Unverricht-Lundborg chromosomes: evidence for a few founder mutations.

Unverricht-Lundborg disease (ULD) is a progressive myoclonus epilepsy common in Finland and North Africa, and less common in Western Europe. ULD is mostly caused by expansion of a dodecamer repeat in the cystatin B gene ( CSTB) promoter. We performed a haplotype study of ULD chromosomes (ULDc) with the repeat expansion. We included 48 West European Caucasian (WEC) and 47 North African (NA) ULDc. We analysed eight markers flanking CSTB(GT10-D21S1890-D21S1885-D21S2040-D21S1259- CSTB-D21S1912-PFKL-D21S171) and one intragenic variant in the CSTB 3' UTR (A2575G). We observed a founder effect in most of the NA ULD patients, as 61.7% of the NA ULDc (29/47) shared the same haplotype, A1 (1-1-A-1-6-7), for markers D21S1885-D21S2040-A2575G-D21S1259-D21S1912-PFKL. Moreover, if we considered only the markers D21S1885, D21S2040, A2575G and D21S1259, 43 of the 47 NA ULDc shared the same alleles 1-1-A-1, haplotype A. As previously shown, the WEC ULDc were heterogeneous. However, the Baltic haplotype, A3 (5-1-1-A-1-1), was observed in ten WEC ULDc (20.8%) and the CSTB 3'UTR variant, which we called the Alps variant, was observed in 17 ULDc (35.4%). Finally, as almost all NA patients, like Scandinavian patients, were of the haplotype A, we assumed that there was an ancient common founder effect in NA and Baltic ULD patients. We estimated that the putative most recent common ancestral ULD carrier with this haplotype A must have existed about 2,500 years ago (100-150 generations). Finally, this work provides evidence for the existence of only a small number of founder mutations in ULD.