Lucio Parmeggiani

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

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.

Topiramate and its clinical applications in epilepsy

Topiramate, a derivative of the monosaccharide d-fructose, has shown a wide spectrum of antiepileptic efficacy in both animal models and clinical trials. Multiple putative mechanisms of action include voltage-sensitive sodium channel blockade, calcium channel inhibition, increase of potassium conductance, GABA-mediated chloride current increment, glutamate-mediated neurotransmission inhibition and carbonic anhydrase isoenzyme inhibition. In general, the clinical response is maintained in the long-term. The most common side effects include somnolence, fatigue, headache, psychomotor slowing, confusion, difficulty with memory, impaired concentration and attention, speech and language problems and weight loss. If slowly titrated and used at a low-to-medium dosage, it is well tolerated and offers a valid therapeutic option, the relevance of which is comparable to that of the most widely used ‘old’ antiepileptic drugs. As it is not yet wholly clear which specific epilepsy syndromes may benefit most from topiramate with respect to other drugs, more accurate indications for initial monotherapy would require syndrome-oriented trials and more clinical experience.

Early‐onset Absence Epilepsy and Paroxysmal Dyskinesia

Summary:  Purpose: To report on the association of childhood absence epilepsy and paroxysmal dyskinesia (PD).

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.

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.

Nonsyndromic mental retardation and cryptogenic epilepsy in women with doublecortin gene mutations

DCX mutations cause mental retardation in male subjects with lissencephalypachygyria and in female subjects with subcortical band heterotopia (SBH). We observed four families in which carrier women had normal brain magnetic resonance imaging (MRI) and mild mental retardation, with or without epilepsy. Affected male subjects had SBH or pachygyria‐SBH. In two families, the phenotype was mild in both genders. In the first family, we found a tyr138his mutation that is predicted to result in abnormal folding in the small hinge region. In the second family, we found an arg178cys mutation at the initial portion of R2, in the putative β‐sheet structure. Carrier female subjects with normal MRI showed no somatic mosaicism or altered X‐inactivation in lymphocytes, suggesting a correlation between mild mutations and phenotypes. In the two other families, with severely affected boys, we found arg76ser and arg56gly mutations within the R1 region that are predicted to affect DCX folding, severely modifying its activity. Both carrier mothers showed skewed X‐inactivation, possibly explaining their mild phenotypes. Missense DCX mutations may manifest as non‐syndromic mental retardation with cryptogenic epilepsy in female subjects and SBH in boys. Mutation analysis in mothers of affected children is mandatory, even when brain MRI is normal. Ann Neurol 2003

Focal seizures with affective symptoms are a major feature of PCDH19 gene-related epilepsy

Purpose:  Mutations of the protocadherin19 gene (PCDH19) cause a female‐related epilepsy of variable severity, with or without mental retardation and autistic features. Despite the increasing number of patients and mutations reported, the epilepsy phenotype associated with PCDH19 mutations is still unclear. We analyzed seizure semiology through ictal video–electroencephalography (EEG) recordings in a large series of patients.

Adolescent Onset of Idiopathic Photosensitive Occipital Epilepsy After Remission of Benign Rolandic Epilepsy

Summary: 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.

Evaluation of carisbamate, a novel antiepileptic drug, in photosensitive patients: an exploratory, placebo-controlled study.

PURPOSE Carisbamate, a novel neuromodulatory agent with antiepileptic properties, was evaluated in patients with photoparoxysmal responses to intermittent photic stimulation (IPS) in this multicenter, non-randomized, single-blind, placebo-controlled, proof-of-concept study. METHODS Eighteen Caucasian patients (14 females, 4 males) with a mean age of 30 years (range: 16-51 years) underwent standardized IPS under three eye conditions (during eye closure, eyes closed and eyes open) at hourly intervals for up to 8h after receiving placebo (Day 1), carisbamate (Day 2) and placebo (Day 3). Carisbamate was given at single doses of 250-1000 mg. All patients received one or two concomitant antiepileptic drugs, most commonly valproate. RESULTS Carisbamate produced a dose-dependent reduction in photosensitivity in the 13 evaluable patients, with abolishment of photoparoxysmal responses in 3 patients and clinically significant suppression of such responses in 7 additional patients. Photosensitivity was abolished or reduced in all five patients in the 1000-mg dose group. The onset of carisbamate occurred rapidly, with clinically significant suppression achieved before or near the time peak plasma drug levels were reached. The duration of action was dose-related and long-lasting, with clinically significant reductions of photosensitivity observed for up to 32 h after doses of 750 or 1000 mg. Carisbamate was generally well tolerated, with dizziness and nausea reported more frequently after active drug than placebo. CONCLUSION This study shows that carisbamate exhibits dose-related antiepileptic effects in the photosensitivity model. Randomized, controlled studies of carisbamate in epilepsy patients inadequately controlled by their existing AED therapy are warranted.