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ENM is an etiologically heterogeneous disorder clinically evident as brief (less than 500 msec) lapses of tonic muscular contraction which seems to be related to lesions or dysfunction of different anatomofunctional levels of the CNS (Fig. 13). ENM can occur in heterogeneous epileptic disorders, ranging from benign syndromic conditions (such as BECTS) to focal static lesional epilepsy, as in neuronal migration disorders, and even to severe static or progressive myoclonic encephalopathies (PMEs). Neurophysiological studies in patients with ENM lead to the following conclusions: 1. A cortical origin of ENM is supported by EEG mapping and dipole analysis of spikes related to the ENM. In particular, our data suggest that the focal spike is a paroxysmal event involving, primarily or secondarily, the centroparietal and frontal "supplementary" motor areas. 2. A cortical inhibitory active mechanism for the genesis of ENM is supported by the occurrence of a decreased motor response to TMS, with preserved spinal excitability as demonstrated by the persistence of F waves. A "cortical motor outflow inhibition" related to spike-and-wave discharges was suggested by Gloor in his Lennox lecture (34). The cortical reflex negative myoclonus, described by Shibasaki et al. (16) in PME, is also consistent with a cortical active inhibitory mechanism. The spike associated with ENM raises new issues about the definition of "interictal" versus "ictal" EEG paroxysmal activity. A single spike on the EEG can be clinically silent (therefore, "interictal") or clinically evident as ENM (then viewed as "ictal"), depending on whether a given group of muscles is at rest or is showing tonic activity (see Fig. 4). These data, from a more general perspective, imply that the motor manifestation related to EEG paroxysmal events can depend not only on amplitude, topography, or intracortical distribution of seizure activity (35), but also on plasticity (36) and on the functional condition of the motor system (37). The variability of latency between the spike and the onset of the muscular inhibition (ranging from 15 to 50 msec, for the upper limbs), and the variability of duration of the ENM itself (from 50 to 400, or more, msec) indicate that ENM could be the result of inhibitory phenomena arising not only from a single cortical "inhibitory" area, but also from subcortical and pontine structures, as discussed by Mori et al. (this volume). The neurophysiological distinction between ENM and postmyoclonic periods of muscular suppression, mainly related to an EGG slow wave, as described by Lance and Adams (2) in the postanoxic action myoclonus is still a matter of discussion (38, 39). This is also the case for other movement disorders combining action myoclonus and epilepsy-as described in Ramsay Hunt syndrome (30), now better referred to as Unverricht-Lundborg syndrome (40) (Fig. 14). In these conditions, myoclonia and muscular silent periods are inconstantly associated with paroxysmal EEG discharges, suggesting a possible thalamocortical mechanism rather than a purely cortical one. In the most prolonged muscular inhibitions, both cortical and thalamocortical mechanisms might be implicated. Clearly, our knowledge of ENM is still very limited and gaining further insights into this complex phenomenon is a challenging problem.

A wide phenotypic spectrum of neurological diseases is associated with KCNA1 (Kv1.1) variants. To investigate the molecular basis of such a heterogeneous clinical presentation and identify the possible correlation with in vitro phenotypes, we compared the functional consequences of three heterozygous de novo variants (p.P403S, p.P405L, and p.P405S) in Kv1.1 pore region found in four patients with severe developmental and epileptic encephalopathy (DEE), with those of a de novo variant in the voltage sensor (p.A261T) identified in two patients with mild, carbamazepine-responsive, focal epilepsy. Patch-clamp electrophysiology was used to investigate the functional properties of mutant Kv1.1 subunits, both expressed as homomers and heteromers with wild-type Kv1.1 subunits. KCNA1 pore mutations markedly decreased (p. P405S) or fully suppressed (p. P403S, p. P405L) Kv1.1-mediated currents, exerting loss-of-function (LoF) effects. By contrast, channels carrying the p.A261T variant exhibited a hyperpolarizing shift of the activation process, consistent with a gain-of-function (GoF) effect. The present results unveil a novel correlation between in vitro phenotype (GoF vs LoF) and clinical course (mild vs severe) in KCNA1-related phenotypes. The excellent clinical response to carbamazepine observed in the patients carrying the A261T variant suggests an exquisite sensitivity of KCNA1 GoF to sodium channel inhibition that should be further explored.

We prospectively examined the effect of antiepileptic (AED) cotherapy on steady state plasma concentrations of perampanel (PMP) in epileptic patients. We classified AEDs as strong enzyme inducers (carbamazepine, phenobarbital, phenytoin, oxcarbazepine), not strong enzyme inducers/not inhibitors (levetiracetam, lamotrigine, topiramate, rufinamide, lacosamide, zonisamide, clobazam), and enzyme inhibitors (valproic acid [VPA]). The main outcome was the comparison of PMP plasma concentration to weight-adjusted dose ratio (C/D; [μg/mL]/mg kg-1 d-1 ) among comedication subgroups. From 79 patients (42 females, 37 males) aged (mean ± standard deviation) 33 ± 13 years (range = 12-66 years), 114 plasma samples were collected. Twenty-eight patients (44 samples) were cotreated with enzyme inducers (group A), 21 (27 samples) with not strong enzyme inducers/not inhibitors (group B), 21 (31 samples) with not strong enzyme inducers/not inhibitors + VPA (group C), and 9 (12 samples) with enzyme inducers + VPA (group D). PMP C/D was reduced (-56%, P

Objectives Myocardial adenosine is increased in pressureoverload hypertrophy (POH) and exerts important cardioprotective effects that delay transition to left ventricular failure. Adenosine-mediated signaling is attenuated in POH, but whether this depends on receptor or postreceptor defects is unknown. We therefore examined left ventricular adenosine A(1)-receptor gene and protein expression in experimental POH. Methods Six week-old Sprague-Dawley rats were subjected to abdominal aortic banding (group B) or sham operation (group S). Echocardiography and left ventricular catheterization were performed 10 weeks later under ketamine anesthesia. Left ventricular and lung weight indices were obtained postmortem. A(1)-Receptor mRNA and protein expression were measured in samples from left ventricular, right ventricular and aortic arch tissue. Group B rats were subgrouped as having compensated or decompensated hypertrophy according to the absence or presence of lung congestion (lung weight index below or above mean +/- 2SD compared with group S rats). Results Both mRNA and protein A-I-receptor expression were significantly increased in compensated group B versus group S rats (by, respectively, 37 and 77%; both P < 0.01). This was not observed in decompensated group B rats. No consistent gene or receptor expression changes were observed in right ventricular or aortic tissues. Conclusions In compensated POH, increased interstitial adenosine concentrations are accompanied by increased expression of the specific receptor mediating the major cardioprotective effects of this autacoid. Such overexpression is no longer detectable once the transition from POH to left ventricular failure has occurred. These observations may have pathophysiological and, in perspective, therapeutic relevance to the course of hypertensive heart disease. J Hypertens 25:449-454 (c) 2007 Lippincott Williams & Wilkins.

Aloe contains several active compounds including aloin, a C-glycoside that can be hydrolyzed in the gut to form aloe-emodin anthrone which, in turn, is auto-oxidized to the quinone aloe-emodin. On the basis of the claimed hepatoprotective activity of some antraquinones, we studied aloe-emodin in a rat model of carbon tetrachloride (CCl 4 ) intoxication, since this xenobiotic induces acute liver damage by lipid peroxidation subsequent to free radical production. Twelve rats were treated with CCl 4 (3 mg/kg) intraperitoneally and six were protected with two intraperitoneally injections of aloe-emodin (50 mg/kg: CCl 4 +aloe-emodin); six other rats were only aloe-emodin injected (aloe-emodin) and six were untreated (control). Histological examination of the livers showed less marked lesions in the CCl 4 +aloe-emodin rats than in those treated with CCl 4 alone, and this was confirmed by the serum levels of L-aspartate-2-oxoglutate-aminotransferase (394±38.6 UI/l in CCl 4 , 280±24.47 UI/l in CCl 4 +aloe-emodin rats; P

We describe a pedigree in which 3 members in the same generation are affected by Rolandic epilepsy (RE), paroxysmal exercise-induced dystonia (PED), and writer's cramp (WC), Both the seizures and paroxysmal dystonia had a strong age-related expression that peaked during childhood, whereas the WC, also appearing in childhood has been stable since diagnosis. Genome-wide linkage analysis performed under the assumption of recessive inheritance identified a common homozygous haplotype in a critical region spanning 6 cM between markers D16S3133 and D16S3131 on chromosome 1.6,. cosegregating with the affected phenotype and producing a multipoint LOD score value of 3.68. Although its features are unique, this syndrome presents striking analogies with the autosomal dominant infantile convulsions and paroxysmal coreoathetosis (ICCA) syndrome, linked to a 10 cM region between D16S401 and D16S517, which entirely includes the 6 cM of the RE-PED-WC critical region. The same gene map be responsible for both RE-PED-WC and ICCA, with specific mutations explaining each of these Mendelian disorders. This report shows that idiopathic focal disorders such as epilepsy and dystonia, can. be caused by: the same genetic abnormality, may have a transient expression, and may be inherited as an autosomal recessive trait.

We describe a pedigree in which eight individuals presented with a non-progressive disorder with onset between the ages of 12 and 50 years. It was characterized by predominantly distal, semi-continuous rhythmic myoclonus (all patients), generalized tonic-clonic seizures (all patients) and complex partial seizures (three patients). Most individuals had rarely suffered seizures and had a normal cognitive level, but three individuals with intractable seizures had mild mental retardation. The pattern of inheritance was autosomal dominant with high penetrance. We defined this disorder as autosomal dominant cortical myoclonus and epilepsy (ADCME). All patients had frontotemporal as well as generalized interictal EEG abnormalities. A neurophysiological study of the myoclonus suggested a cortical origin. Back-averaging of the data generated a series of waves with a frequency that mirrored the frequency of EMG bursts. Frequency analysis identified significant peaks with coherence between EMG and EEG, which were recorded over the contralateral rolandic area in five patients. The frequency of coherence was 8-25 Hz and phase spectra confirmed that EEG activity preceded EMG activity by 8-15 ms. In two individuals there was also significant coherence between the ipsilateral EEG and EMG, consistent with the transcallosal spread of myoclonic activity. The C-reflex at rest was enhanced and somatosensory and visual evoked potentials were of high amplitude. The resting motor threshold intensity to transcranial magnetic stimulation was significantly reduced (38%; SD +/- 7; P = 0.01) and the post-motor evoked potential silent period (101 ms; SEM +/- 10) was significantly shortened compared with the controls (137 ms; SEM +/- 18). These clinical and neuro- physiological characteristics suggest diffuse cortical hyperexcitability and high propensity for intra-hemispheric and inter-hemispheric cortical spread, as well as rhythmic myoclonic activity. Genome-wide linkage analysis identified a critical region spanning 12.4 cM between markers D2S2161 and D2S1897 in 2p11.1-q12.2, with a maximum two-point LOD score of 3.46 at Theta 0.0 for marker D2S2175. Multipoint LOD score values, reaching 3.74 around D2S2175, localize the ADCME gene to the centromeric region of chromosome 2. The exclusion of the locus for familial adult myoclonic epilepsy on chromosome 8q23.3-q24 from linkage to our family and the new localization of the responsible gene to chromosome 2cen, together with the different phenotype, define a new epilepsy syndrome. We hypothesize that the responsible gene causes cortical hyperexcitability that is widespread but particularly involves the frontotemporal circuits.