Early onset developmental and epileptic encephalopathy and Rett-like phenotype in a 15-year-old girl affected by Cornelia de Lange syndrome type 2 due to a SMC1A gene mutation.

Developmental and epileptic encephalopathies (DEE) are conditions in which a mutated gene may cause abnormal functioning of the central nervous system, resulting in both encephalopathy and epileptogenesis. We present a case of a girl with a DEE characterized by a Rett-like phenotype in association with febrile and afebrile clusters of focal seizures. The girl presented typical development until the age of 18 months, followed by regression. The first febrile bilateral tonic-clonic seizure was observed at 30 months of age, and the following month seizures recurred in clusters of several episodes per day every 10 days. These seizures were characterized by behavioural arrest, emotional symptoms, head turning, and followed by bilateral tonic-clonic seizures. The administration of valproic acid and levetiracetam led to prolonged seizure control. However, from the age of 7 years, she had monthly recurrent clusters of focal seizures and non-convulsive status epilepticus which occurred at different ages. Brain and spinal cord MRI showed mild non-progressive hemispheric cerebellar atrophy. A next generation sequencing panel for epilepsy identified the de novo splicing mutation c.2973+1G>A of the SMC1A gene.

Protocadherin 19 mutations in girls with infantile-onset epilepsy.

OBJECTIVE: To explore the causative role of PCDH19 gene (Xq22) in female patients with epilepsy. METHODS: We studied a cohort of 117 female patients with febrile seizures (FS) and a wide spectrum of epilepsy phenotypes including focal and generalized forms with either sporadic or familial distribution. RESULTS: PCDH19 screening showed point mutations in 13 probands (11%). Mean age at seizure onset was 8.5 months; 8 patients (62%) presented with FS, 4 (33%) with cluster of focal seizures, and 1 with de novo status epilepticus (SE). Subsequent seizure types included afebrile tonic-clonic, febrile, and afebrile SE, absences, myoclonic, and focal seizures. Seven patients (54%) had a clinical diagnosis consistent with Dravet syndrome (DS); 6 (46%) had focal epilepsy. In most patients, seizures were particularly frequent at onset, manifesting in clusters and becoming less frequent with age. Mental retardation was present in 11 patients, ranging from mild (7; 64%) to moderate (1; 9%) to severe (3; 27%). Five patients (38%) had autistic features in association to mental retardation. Mutations were missense (6), truncating (2), frameshift (3), and splicing (2). Eleven were new mutations. Mutations were inherited in 3 probands (25%): 2 from apparently unaffected fathers and 1 from a mother who had had generalized epilepsy. CONCLUSIONS: PCDH19 is emerging as a major gene for infantile-onset familial or sporadic epilepsy in female patients with or without mental retardation. In our cohort, epileptic encephalopathy with DS-like features and focal epilepsy of variable severity were the associated phenotypes and were equally represented.

Abnormal corticomuscular and intermuscular coupling in high-frequency rhythmic myoclonus.

Frequency analysis may have some advantages over back-averaging in the neurophysiological assessment of patients with suspected cortical myoclonus in whom myoclonic EMG bursts repeat rhythmically at high frequency. However, the clinical utility of EEG-EMG coherence and related EMG-EMG coherence is not established. Equally, there is an incomplete understanding of the physiology of the systems contributing to the coherence evident between signals in cortical myoclonus. Here we address these issues in an investigation of EEG-EMG and EMG-EMG coupling in proximal and distal muscles of the upper extremities in nine patients with multifocal high frequency rhythmic myoclonus due to non-progressive conditions. We found exaggerated coherence between EEG and contralateral EMG and between pairs of ipsilateral EMG signals. The results of frequency analysis of EMG-EMG mirrored those for EEG-EMG, but the former technique was superior in distinguishing a pathologically exaggerated common drive in distal upper limb muscles. Both techniques were more sensitive than back-averaging. Frequency analysis also revealed important disparities between proximal and distal upper limb muscles. In the latter case, the functional coupling between cortex and muscle was dominated by efferent processes. In contrast, there was considerable inter-individual variation in the extent to which EEG-EMG and EMG-EMG coupling in proximal muscles reflected afferent and efferent loops. Thus, the processes sustaining myoclonic discharges may differ for proximal and distal muscles and between patients.

Autosomal dominant cortical myoclonus and epilepsy (ADCME) with complex partial and generalized seizures: A newly recognized epilepsy syndrome with linkage to chromosome 2p11.1-q12.2.

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.

Autosomal recessive polymicrogyria with infantile spasms and limb deformities.

We describe two siblings, a girl and a boy, aged 4 and 2 years and 10 months respectively, born from non-consanguineous parents,with diffuse polymicrogyria, lower limb deformities, infantile spasms and developmental delay. Spasms had a good outcome under antiepileptic drug treatment. Clinical and imaging features were of identical severity in both siblings. Muscle biopsy,creatine kinase, metabolic investigations and chromosomal analysis were normal. This combination of anatomo-clinical features and their occurrence in siblings of both sexes suggests an autosomal recessive malformation syndrome.

Aloe-Emodin quinone pretreatment reduces acute liver injury induced by carbon tetrachloride.

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 (CCl4) intoxication, since this xenobiotic induces acute liver damage by lipid peroxidation subsequent to free radical production. Twelve rats were treated with CCl4 (3 mg/kg) intraperitoneally and six were protected with two intraperitoneally injections of aloe-emodin (50 mg/kg; CCl4+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 CCl4+aloe-emodin rats than in those treated with CCl4 alone, and this was confirmed by the serum levels of L-aspartate-2-oxoglutate-aminotransferase (394+/-38.6 UI/l in CCl4, 280+/-24.47 UI/l in CCl4+aloe-emodin rats; P<0.05). We also quantified changes in hepatic albumin and tumour necrosis factor-alpha mRNAs. Albumin mRNA expression was significantly lower only in the liver of CCl4 rats (P<0.05 versus control) and was only slightly reduced in the CCl4+aloe-emodin rats. In contrast tumour necrosis factor-alpha mRNA was significantly higher (P<0.05) in the CCl4 than the control rats and almost equal in the CCl4+aloe-emodin, aloe-emodin and control groups. In conclusion, aloe-emodin appears to have some protective effect not only against hepatocyte death but also on the inflammatory response subsequent to lipid peroxidation.

Add-on lamotrigine treatment in children and young adults with severe partial epilepsy: an open, prospective, long-term study.

We evaluated the efficacy and safety of lamotrigine in 41 children and young adults (age range, 3-25 years; mean, 12 years) with drug-resistant, partial epilepsies, based on a prospective, add-on study. Patients had severe symptomatic/cryptogenic partial epilepsies (mean seizure frequency = 3.6/day), resistant to one to four major antiepileptic drugs. Mean seizure frequency significantly decreased (P < .001) throughout the period of treatment. A good response (>50% seizure reduction) was observed in 15 patients of whom 6 were seizure-free (follow-up: 12-48 months). Higher responder rate was found among cryptogenic epilepsies and epilepsies symptomatic of cerebral malformation, whereas patients with posthypoxic-ischemic perinatal damage were poor responders. Lamotrigine discontinuation was mainly due to lack of efficacy (46% of patients), whereas only 2 patients developed a transient skin rash and did not drop out. Lamotrigine represents a valuable treatment for severe partial epilepsies of childhood that have proved resistant to previous antiepileptic drugs.

Myoclonic status epilepticus following high-dosage lamotrigine therapy.

An 8-year-old girl with Lennox-Gastaut syndrome showed a partial reduction in seizure frequency when lamotrigine (LTG), 15 mg/kg per day, was added to clobazam (CLB) and vigabatrin (VGB). An increase in LTG dosage to 20 mg/kg per day produced no further improvement and was followed by myoclonic status epilepticus. The condition developed insidiously and ultimately became stable. Video-EEG polygraphy and jerk-locked back-averaged EEG demonstrated continuous myoclonus of cortical origin. Discontinuation of LTG resulted in rapid disappearance of clinical and electrophysiological manifestations of myoclonic status epilepticus. No episodes of myoclonus occurred in the subsequent 2 years, during which CLB and VGB were kept unchanged. The striking response to drug discontinuation suggests that LTG may have played a role in the precipitation of status, possibly within the context of paradoxical intoxication.

One-year results of a smoking-cessation programme.

We evaluated the effectiveness of a smoking-cessation programme in all patients included between February 1991 and December 1995. After 4 one-hour consultations once a week, 56.2% of patients had quit. Six months later, this rate was between 20 and 25% and few relapses occurred between the 6th and the 12th month. However, the relapse rate was about 50% between the 1st and the 6th month after the consultations and patients certainly need more support during this critical period. In the present study, the 12-month abstinence rate was unrelated to gender, age, and presence of a smoking-related disease. Patients who participated in at least 3 of the 4 sessions of the course had a significantly higher smoking-cessation rate.

Autosomal recessive rolandic epilepsy with paroxysmal exercise-induced dystonia and writer's cramp: delineation of the syndrome and gene mapping to chromosome 16p12-11.2.

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 16, 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 may 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.

Idiopathic partial epilepsy: electroclinical demonstration of a prolonged seizure with sequential rolandic and occipital involvement. Seizure spread due to regional susceptibility?

Benign rolandic epilepsy (BRE) and childhood epilepsy with occipital paroxysms (CEOP) are overlapping in age range of presentation. Some children have been reported to manifest occipital and rolandic seizures, as distinct events. However, the presence during the same seizure of rolandic and occipital symptoms is exceptional. We present a 7-year-old boy with BRE in whom we video-EEG recorded two seizures at 4 years of age. The first episode was a classic rolandic seizure during sleep, while the second was prolonged with initial rolandic and late occipital involvement. It is possible that a rolandic seizure, in a child within the age range of both BRE and early onset CEOP, could spread to selectively involve the occipital lobe, because there is susceptibility of cortical neurons of both areas to develop seizures at this age in idiopathic partial epilepsies.

Cortical reflex myoclonus in Rett syndrome.

Rett syndrome (RS) is one of the most frequent causes of mental retardation in females. As there are no known biochemical, genetic, or morphological markers, diagnosis is based on clinical phenotype including severe dementia, autism, truncal ataxia/apraxia, loss of purposeful hand movements, breathing abnormalities, stereotypies, seizures, and extrapyramidal signs. Myoclonus, although reported in some series, has never been characterized. We studied 10 RS patients, age 3 to 20 years, and observed myoclonus in 9. Severity of myoclonus did not correlate with that of the other symptoms or with age. Multifocal, arrhythmic, and asynchronous jerks mainly involved distal limbs. Electromyographic bursts lasted 48 +/- 12 msec. Burst-locked electroencephalographic averaging generated a contralateral centroparietal premyoclonus transient preceding the burst by 34 +/- 7.2 msec. Motor evoked potentials showed normal latencies, indicating integrity of the corticospinal pathway. Somatosensory evoked potentials were enlarged. The C-reflex was hyperexcitable and markedly prolonged (62 +/- 4.3 msec), mainly due to increase in cortical relay time (28.4 +/- 4.5 msec). We conclude that RS patients show a distinctive pattern of cortical reflex myoclonus with prolonged intracortical delay of the long-loop reflex.

Adolescent onset of idiopathic photosensitive occipital epilepsy after remission of benign rolandic epilepsy.

PURPOSE: We describe 2 girls, aged 19 years, who experienced a rolandic seizure at ages 4 and 5, respectively, together with the interictal EEG features of benign rolandic epilepsy (BRE). In adolescence both patients developed photosensitive occipital seizures accompanied by spontaneous and photic-induced occipital EEG paroxysms. METHODS: We have been following 33 patients with a history of BRE, between ages 12 and 28 years (mean 17 years). Twenty-one of these patients had experienced their last rolandic seizure before the age of 10 years and 9 of them had been without treatment since age 11 or earlier. In 2 of these 9 patients, other types of seizures recurred after remission of BRE. Clinical, EEG, and evoked potential findings on these 2 patients are presented. RESULTS: After having experienced BRE, both patients suffered partial seizures from age 12, with elementary visual hallucinations, visual blurring, slow head turning, cephalic pain, epigastric discomfort, unresponsiveness, and vomiting. Seizure onset was related to watching TV or exposure to bright light. EEG showed interictal occipital spikes, and a photoparoxysmal response limited to the occipital lobes. Visual evoked potentials were greatly increased in amplitude. One patient had two visual attacks only and remained seizure free after 4 years of follow-up, while the other had seizures controlled by an association of valproate and carbamazepine. CONCLUSIONS: Clinical and neurophysiological characteristics suggest that these two patients may have presented different age-related expressions within the spectrum of a benign seizure susceptibility syndrome rather than sharply distinct epilepsy syndromes.

Electroclinical features of idiopathic generalised epilepsy with persisting absences in adult life.

OBJECTIVES: To describe the electroclinical features of typical absences persisting in adult life. METHODS: Twelve adult patients (aged 21 to 56 years) with idiopathic generalised epilepsy featuring typical absences as the prominent clinical feature were studied. All patients underwent a full clinical and neurophysiological investigation including ictal documentation of seizures. RESULTS: Neurological examination and neuroradiological investigations were normal in all cases. Clinical findings included a median age at onset of absences of 14 (range 4-32) years, almost constant tonic-clonic seizures (in 83% of patients), frequent episodes of absence status (in 33% of patients), and associated cognitive or psychiatric disturbances. Interictal EEG findings showed normal background activity, generalised paroxysms of spike waves or polyspike waves, and inconstant focal spikes (in five patients); runs of polyspikes were seen during non-REM sleep. Ictal EEG findings showed generalised spike waves at 3 Hz, sometimes preceded by multiple spikes, or more complex EEG patterns with sequences of polyspikes intermingled with spike waves or polyspike waves, showing discharge fragmentation or variation of intradischarge frequency. CONCLUSION: The results of the present study show that absences persisting in adult life may show particular clinical and EEG patterns, distinct from those in childhood or adolescence.

Dipole-modeling of the visual evoked P300.

We collected visual event-related potentials (ERPs) from 6 normal subjects using an "oddball" paradigm. Subjects were required to count the occurrences of matching shapes presented in the left and right visual field. Shapes matched on 20% of trials. ERPs were recorded from 20 or 43 electrodes distributed over the scalp. A multiple spatio-temporal equivalent dipole (ED) model was used to fit the early sensory and P300 component. A latency window to analyze the P300 was determined using the global field power statistic. The spatial topography of the P300 over this window was characterized by a midline positivity that decreased in amplitude with spatial distance from the peak. After sensory components were fit, the source of P300 could be accounted for by 1 or 2 EDs, which were usually located near medial temporal areas. This result is at odds with evidence from depth recordings during the oddball paradigm, showing that multiple regions of the brain are active during this interval.

The effects of luminance and chromatic background flicker on the human visual evoked potential.

Previous studies report that background luminance flicker, which is asynchronous with signal averaging, reduces the amplitude and increases the latency of the pattern-onset visual evoked potential (VEP). This effect has been attributed to saturation of the magnocellular (m-) pathway by the flicker stimulus. In the current study, we evaluate this hypothesis and further characterize this effect. We found that flicker had similar effects on the pattern-onset and pattern-reversal VEP, suggesting that the reversal and onset responses have similar generators. Chromatic flicker decreased latency of the chromatic VEP whereas luminance flicker increased peak latency to luminance targets. This result indicates that luminance flicker saturates a rapidly conducting m-pathway whereas chromatic flicker saturates a more slowly conducting parvocellular (p-) pathway. Finally, evoked potentials to chromatic and luminance stimuli were recorded from 34 electrodes over the scalp in the presence of static and asynchronously modulated backgrounds. An equivalent dipole model was used to assess occipital, parietal, and temporal lobe components of the surface response topography. Results showed that chromatic flicker reduced activity to a greater extent in the ventral visual pathway whereas luminance flicker reduced activity to a greater extent in the dorsal visual pathway to parietal lobe. We conclude that the VEP to isoluminant color and luminance stimuli contains both m- and p-pathway components. Asynchronous flicker can be used to selectively reduce the contribution of these pathways to the surface recorded VEP. Our results provide evidence of parallel pathways in the human visual system, with a dorsal luminance channel projecting predominantly to the posterior parietal lobe and a ventral color channel projecting predominantly to inferior temporal lobe.