Paolo Bonanni

Idiopathic photosensitive occipital lobe epilepsy.

Summary: We studied 10 neurologically normal patients (8 females, 2 males) aged 8–30 years (mean 17 years) who had recurrent episodes of visually induced occipital seizures. Television and computer screens were the main triggers. Seizure onset occurred between the ages of 5 and 17 years (mean 11 years). All seizures were stimulus related and began with elementary visual symptoms, followed in most patients by a slow clustering of cephalicpain, epigastric discomfort, and vomiting, with either normal or only mildly impaired responsiveness. EEG fea‐tures included normal background activity, occipital spikes and waves, and a photoparoxysmal response which could be occipital, generalized, or both. Four pa‐tients also showed spontaneous generalized epileptiform abnormalities, and 3 had rolandic spikes. An Oz electrode was critical in identifying epileptiform activity in some patients. Complete seizure control was achieved in most patients with monotherapy, although occasional stimulus‐related seizures occurred in 3 patients who showed a wider range of photosensitivity. These patients have an idiopathic localization‐related epilepsy with age‐related onset and specific mode of precipitation. Although this type of epilepsy has been reported previously, it has remained underrecognized, probably because it is difficult to differentiate clinically from migraine or from nonreflex childhood idiopathic occipital epilepsy.

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 writers 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. Ann Neurol 1999;45:344–352

Multilobar polymicrogyria, intractable drop attack seizures, and sleep-related electrical status epilepticus.

Background and Objective: Patients with cortical malformations often have intractable seizures and are candidates for epilepsy surgery. Within an unselected series of patients with various forms of cortical malformation, nine patients with multilobar polymicrogyria had electrical status epilepticus during sleep (ESES) accompanied by infrequent focal motor seizures. Eight patients also had intractable atonic drop attack seizures. Because ESES usually is accompanied by a good long-term seizure prognosis, the objective of this study was to examine ESES outcome among patients with a structural lesion that is usually highly epileptogenic and has a low seizure remission trend. Methods: The nine patients had follow-up periods lasting 4 to 19 years. All underwent brain MRI, serial sleep EEG recordings, and cognitive testing during and after ESES. Results: ESES and drop attack seizures appeared between the ages of 2 and 5 years(mean, 4 years) and ceased between the ages of 5 and 12 years (mean, 8 years). At the last visit patients were 8 to 23 years of age (mean, 14.5 years) and were either seizure free or had very infrequent focal motor seizures during sleep. Three patients were free from antiepileptic drugs. In no patient was definite cognitive deterioration apparent after ESES in comparison with earlier evaluations. Conclusions: Age-related secondary bilateral synchrony underlying ESES may be facilitated in multilobar polymicrogyria. The good seizure outcome contrasts with that usually found in the presence of cortical malformations. For children with polymicrogyria and drop attack seizures, surgical treatment of the epilepsy should be considered cautiously, and sleep EEG recordings should be performed systematically.

Lack of cortical contrast gain control in human photosensitive epilepsy

Television and video games may be powerful triggers for visually induced epileptic seizures. To better understand the triggering elements of visual stimuli and cortical mechanisms of hyperexcitability, we examined eleven patients with idiopathic photosensitive epilepsy by recording visually evoked potentials (VEPs) in response to temporally modulated patterns of different contrast. For stimuli of low–medium, but not high, temporal frequency, the contrast dependence of VEP amplitude and latency is remarkably abnormal for luminance contrast (black–white), but not so for chromatic contrast (equiluminant red–green) stimuli. We conclude that cortical mechanisms of contrast gain control for pattern stimuli of relatively low temporal frequency and high luminance contrast are lacking or severely impaired in photosensitive subjects.

Benign Familial Infantile Convulsions: Mapping of a Novel Locus on Chromosome 2q24 and Evidence for Genetic Heterogeneity

In 1997, a locus for benign familial infantile convulsions (BFIC) was mapped to chromosome 19q. Further data suggested that this locus is not involved in all families with BFIC. In the present report, we studied eight Italian families and mapped a novel BFIC locus within a 0.7-cM interval of chromosome 2q24, between markers D2S399 and D2S2330. A maximum multipoint HLOD score of 6.29 was obtained under the hypothesis of genetic heterogeneity. Furthermore, the clustering of chromosome 2q24-linked families in southern Italy may indicate a recent founder effect. In our series, 40% of the families are linked to neither chromosome 19q or 2q loci, suggesting that at least three loci are involved in BFIC. This finding is consistent with other autosomal dominant idiopathic epilepsies in which different genes were found to be implicated.

Angelman syndrome: etiology, clinical features, diagnosis, and management of symptoms.

It is estimated that Angelman syndrome (AS) accounts for up to 6% of all children presenting with severe mental retardation and epilepsy. The main clinical features of AS may not be apparent early in life. Clinical findings present in all patients include developmental delay, which becomes apparent by 6–12 months of age, severely impaired expressive language, ataxic gait, tremulousness of limbs, and a typical behavioral profile, including a happy demeanor, hypermotoric behavior, and low attention span. Seizures, abnormal electroencephalography, microcephaly, and scoliosis are observed in >80% of patients.Approximately 70% of patients show a deletion involving the maternally inherited chromosome 15q11-q13, encompassing a cluster of γ-aminobutyric acid receptor subunit genes, 3% show chromosome 15 paternal uniparental disomy (UPD), 1% harbor a mutation in the imprinting center (a transcriptional regulatory element), and 6% harbor intragenic mutations of the ubiquitin-protein ligase E3A (UBE3A) gene. Twenty percent of patients have no detectable genetic abnormality. Rare cases of familial recurrence of AS show either imprinting center (IC) or UBE3A mutations. Approximately 75% of cases are detected through the methylation test, which allows the detection of AS due to deletions, UPD and IC mutations. Mutation analysis of the UBE3A gene should be performed when the methylation test is negative.Individuals with chromosome 15q11-q13 deletions have a more severe clinical picture and are more prone to develop severe epilepsy. Epilepsy has typical features, including absence and myoclonic seizures, and insidious episodes of nonconvulsive or subtle myoclonic status which are easily overlooked as children appear apathetic or in a state of neurologic regression. Tremulousness, present in all patients even when seizures are well controlled or absent, is related to distal cortical myoclonus. Valproic acid (sodium valproate), benzodiazepines, and ethosuximide, in various combinations, are quite effective in treating the typical seizure types. Piracetam may help in reducing distal myoclonus. Carbamazepine and vigabatrin may seriously aggravate absence and myoclonic seizures and should be avoided.Cognitive, language, and orthopedic problems must be addressed with vigorous rehabilitation programs, including early physical therapy, which may help to develop communicative skills and prevent severe scoliosis and subsequent immobility. Where these treatment strategies are applied, individuals with AS may reach an appreciable level of integration, self care, and have a normal life span.

A nonsense mutation of the ATRX gene causing mild mental retardation and epilepsy.

Mutations in the X‐encoded gene ATRX are known to give rise to profound syndromal mental retardation (MR). Here, we describe a pedigree, including 4 affected family members with a 324C→T nonsense mutation in the ATRX gene. Although 2 patients have moderate to profound MR and the typical facial features of ATR‐X syndrome, the other 2 patients presented with mild MR and epilepsy but without the characteristic facial dysmorphism. Mutations in the ATRX gene should be considered as a cause of mild MR in male patients lacking specific diagnostic features. Ann Neurol 2000; 47:117–121

Electrophysiological characterization of spontaneous and carbamazepine-induced epileptic negative myoclonus in benign childhood epilepsy with centro-temporal spikes.

OBJECTIVE Epileptic negative myoclonus (ENM), a transient muscular atonic phenomenon time-locked to epileptiform EEG abnormalities, is often observed in children with benign childhood epilepsy with centro-temporal spikes (BECTS). In some, for unknown reasons, ENM can be worsened by carbamazepine (CBZ). We describe two children aged 11 and 15 years, in whom CBZ precipitated seizure worsening and ENM. We investigated the morphological and topographic features of the EEG abnormalities while on CBZ and after CBZ withdrawal and compared them with those from 9 children with classical BECTS. The aim of the study was to identify possible electrophysiological specificities in patients who eventually develop ENM during CBZ treatment. METHODS The characterization of EEG abnormalities, related (R) and unrelated to ENM (U), in patients with ENM and rolandic discharges (RD) and in matched controls with BECTS was performed based on polygraphic digital EEG recordings. Off-line time-domain analysis included correlation coefficient between EEG and EMG channels, quantitative analysis on ENM, and topographic analysis on spike-and-wave complexes. Z-score test and paired t test were used when appropriate for statistical analysis on R, U and RD. RESULTS Recordings in both children with BECTS and ENM while on CBZ showed frequent R discharges (mean interval between R=19.89+/-9.4 s in patient 1; 2.16+/-1.2 s in patient 2). Withdrawal of CBZ produced abatement of R (no R recorded in patient 1; 5.69+/-7.1 s in patient 2) and reduction of the slow wave component of R (P<0.01). Morphology and topography of R and RD differed in field distribution, amplitude (P<0.01) and duration (P<0.01) of the slow wave component. RD and U did not show a significantly different morphology and field distribution. CONCLUSIONS Our findings suggest that an increased cortical inhibition could be the electrophysiological correlate of CBZ-induced ENM. If confirmed on a larger series, the presence of spike-wave (rather than sharp waves) discharges in children with BECTS might be used as an electrophysiological predictor of an abnormal response to CBZ.

Physiology of Human Photosensitivity

Summary:  Human epileptic photosensitivity has been studied in several ways. (a) Visual stimulation that resembles the stimulation normally responsible for seizures, such as that from televisions or videogames, both of which typically use cathode ray tubes in which the display is created in a flickering pattern. Such stimulation is often rendered yet more epileptogenic by programmes with content that also involves flashing or patterned material. (b) Elementary visual stimuli that enable inferences to be drawn concerning the physiological trigger mechanisms. The topographic distribution of epileptiform EEG activity in response to such stimuli has complemented this approach, leading to the inference that the trigger is cortical and requires sychronised mass action of neurons. (c) Stimuli that avoid paroxysmal EEG activity and permit an investigation of the subepileptic response to visual stimuli, using the evoked potential. This has revealed abnormalities in the cortical mechanisms that control the response to strong visual stimulation.

Generalized Epilepsy with Febrile Seizures Plus (GEFS+): Clinical Spectrum in Seven Italian Families Unrelated to SCN1A, SCN1B, and GABRG2 Gene Mutations

Summary:  Purpose: We describe seven Italian families with generalized epilepsy with febrile seizures plus (GEFS+), in which mutations of SCN1A, SCN1B, and GABRG2 genes were excluded and compare their clinical spectrum with that of previously reported GEFS+ with known mutations.