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Op 19 december 2022 vond in Utrecht de promotie plaats van Bianca Berghuis, op een proefschrift getiteld: Carbamazepine en Oxcarbazepine Induced Hyponatremia.

De medicamenteuze behandeling van progressieve myoclonus epilepsie is van belang omdat aanvallen een belangrijke invloed hebben op de kwaliteit van leven. Helaas is de epilepsie vaak medicatie-resistent en wordt de prognose van de aandoeningen niet beïnvloed door een anti-aanvalsbehandeling. Hier worden de mogelijkheden besproken voor behandeling die is gericht op de onderliggende genetische en metabole oorzaken.

Objective To ascertain whether adverse effects experienced by people taking carbamazepine or oxcarbazepine could be attributed to carbamazepine‐ or oxcarbazepine‐induced hyponatremia (COIH). Methods We performed an observational study, collecting data between 2017 and 2019 on serum sodium levels and adverse effects retrospectively in people with epilepsy while receiving treatment with either carbamazepine (CBZ) or oxcarbazepine (OXC). We defined hyponatremia as sodium level ≤134 mEq/L and severe hyponatremia as sodium level ≤128 mEq/L. Adverse effects experienced were compared between groups of individuals with and without hyponatremia. Results A total of 1370 people using CBZ or OXC were identified, of whom 410 had at least one episode of hyponatremia. We checked for symptoms related to the use of CBZ and OXC in 710 people (410 with and 300 without hyponatremia) and found relevant information in 688. Adverse effects occurred in 65% of people with hyponatremia compared to 21% with normal sodium levels (odds ratio [OR] 7.5, P ≤ .001) and in 83% of people with severe hyponatremia compared to 55% in those with mild hyponatremia (P ≤ .001). Significant predictors of adverse effects were the drug (OXC vs CBZ), and the number of concomitant anti‐seizure medications. Dizziness (28% vs 6%), tiredness (22% vs 7%), instability (19% vs 3%), and diplopia (16% vs 4%) were reported more often in the hyponatremia group than in patients with normal levels. Significance People with COIH had a 7‐fold increased risk of developing adverse effects during treatment. Clinicians should consider ascertainment of sodium levels in patients taking CBZ and OXC and act upon findings.

Because hyper-excitability has been shown to be a shared pathophysiological mechanism, we used the latest and largest genome-wide studies in amyotrophic lateral sclerosis (n = 36,052) and epilepsy (n = 38,349) to determine genetic overlap between these conditions. First, we showed no significant genetic correlation, also when binned on minor allele frequency. Second, we confirmed the absence of polygenic overlap using genomic risk score analysis. Finally, we did not identify pleiotropic variants in meta-analyses of the 2 diseases. Our findings indicate that amyotrophic lateral sclerosis and epilepsy do not share common genetic risk, showing that hyper-excitability in both disorders has distinct origins. ispartof: NEUROBIOLOGY OF AGING vol:92 ispartof: location:United States status: published

Therapeutic Drug Monitoring (TDM) of anti-epileptic drugs (AEDs) is not routinely performed, although this can guide the dosage regimen to achieve greater efficacy and safety. Levetiracetam (LEV) has been introduced as an AED with an almost perfect pharmacokinetic (PK) profile. Nonetheless, recent research challenges this statement and therefore we aimed to explore factors that modify LEV PK.Age and enzyme-inducing drugs (EIDs) appear to be major factors influencing the PK profile of LEV. Therefore, 30-50% lower dosages should be used in the elderly ( > 65 years of age) and the dosing regimen should be guided by monitoring SDC (TDM). In contrast, higher LEV dosages are necessary in children aged between 2 months and 12 years (compared to adults) due to a 30-70% increase of LEV clearance (CL). Higher dosages are also required if a patient receives EIDs, again due to a higher CL of LEV (range 24-60%). This could also be true for pregnant women.LEV TDM is currently not common in the clinical setting due to the wide therapeutic range and the low prevalence of side-effects. However, LEV dose should on the one hand be increased in certain physiological situations (pregnancy, neonates) and patients on EIDs (especially carbamazepine). On the other hand, dose reductions are necessary when the LEV CL is impaired (elderly). Nevertheless, current data to support regular LEV TDM are lacking. Prospective research is needed to explore the importance of LEV TDM in elected patient groups; i.e. neonates, elderly, patients on EIDs and pregnant women.

Background Progressive myoclonus epilepsies (PMEs) are a group of rare inherited diseases featuring a combination of myoclonus, seizures and variable degree of cognitive impairment. Despite extensive investigations, a large number of PMEs remain undiagnosed. In this review, we focus on the current pharmacological approach to PMEs. Methods References were mainly identified through PubMed search until February 2017 and backtracking of references in pertinent studies. Results The majority of available data on the efficacy of antiepileptic medications in PMEs are primarily anecdotal or observational, based on individual responses in small series. Valproic acid is the drug of choice, except for PMEs due to mitochondrial diseases. Levetiracetam and clonazepam should be considered as the first add-on treatment. Zonisamide and perampanel represent promising alternatives. Phenobarbital and primidone should be reserved to patients with resistant disabling myoclonus or seizures. Lamotrigine should be used with caution due to its unpredictable effect on myoclonus. Avoidance of drugs known to aggravate myoclonus and seizures, such as carbamazepine and phenytoin, is paramount. Psychiatric (in particular depression) and other comorbidities need to be adequately managed. Although a 3- to 4-drug regimen is often necessary to control seizures and myoclonus, particular care should be paid to avoid excessive pharmacological load and neurotoxic side effects. Target therapy is possible only for a minority of PMEs. Conclusions Overall, the treatment of PMEs remains symptomatic (i.e. pharmacological treatment of seizures and myoclonus). Further dissection of the genetic background of the different PMEs might hopefully help in the future with individualised treatment options.

The epilepsies affect around 65 million people worldwide and have a substantial missing heritability component. We report a genome-wide mega-analysis involving 15,212 individuals with epilepsy and 29,677 controls, which reveals 16 genome-wide significant loci, of which 11 are novel. Using various prioritization criteria, we pinpoint the 21 most likely epilepsy genes at these loci, with the majority in genetic generalized epilepsies. These genes have diverse biological functions, including coding for ion-channel subunits, transcription factors and a vitamin-B6 metabolism enzyme. Converging evidence shows that the common variants associated with epilepsy play a role in epigenetic regulation of gene expression in the brain. The results show an enrichment for monogenic epilepsy genes as well as known targets of antiepileptic drugs. Using SNP-based heritability analyses we disentangle both the unique and overlapping genetic basis to seven different epilepsy subtypes. Together, these findings provide leads for epilepsy therapies based on underlying pathophysiology., SCOPUS: ar.j, info:eu-repo/semantics/published

Objective: To ascertain whether characteristics of ventricular tachycardia/fibrillation (VT/VF) differed between people with epilepsy and those without and which individuals with epilepsy were at highest risk. Methods: We ascertained 18 people with active epilepsy identified in a community-based registry of sudden cardiac arrest (SCA) with ECG-confirmed VT/VF (cases). We compared them with 470 individuals with VT/VF without epilepsy (VT/VF controls) and 54 individuals with epilepsy without VT/VF (epilepsy controls). Data on comorbidity, epilepsy severity, and medication use were collected and entered into (conditional) logistic regression models to identify determinants of VT/VF in epilepsy. Results: In most cases, there was an obvious (10/18) or presumed cardiovascular cause (5/18) in view of preexisting heart disease. In 2 of the 3 remaining events, near–sudden unexpected death in epilepsy (SUDEP) was established after successful resuscitation. Cases had a higher prevalence of congenital/inherited heart disease (17% vs 1%, p = 0.002), and experienced VT/VF at younger age (57 vs 64 years, p = 0.023) than VT/VF controls. VT/VF in cases occurred more frequently at/near home (89% vs 58%, p = 0.009), and was less frequently witnessed (72% vs 89%, p = 0.048) than in VT/VF controls. Cases more frequently had clinically relevant heart disease (50% vs 15%, p = 0.005) and intellectual disability (28% vs 1%, p Conclusion: Cardiovascular disease rather than epilepsy characteristics is the main determinant of VT/VF in people with epilepsy in the community. SCA and SUDEP are partially overlapping disease entities.

SUMMARY Little is known about pregnancy-induced alterations in the pharmacokinetics of the newer antiepileptic drugs, especially when used in combinations. Two women receiving combination therapy of lamotrigine (LTG) and oxcarbazepine (OXC) were followed prospectively during pregnancy and puerperium. Steady-state concentrations of LTG and the active metabolite of OXC, 10-hydroxycarbazepine (MHD), were measured at regular intervals using a dried blood spot method, and clearances were calculated. A strong effect of pregnancy on the clearance of both LTG and MHD was seen. An increase in seizure frequency occurred in both women. This stresses the importance of therapeutic drug monitoring of LTG and MHD during pregnancy. In case of breakthrough seizures or increased seizure frequency, dosage adjustment of both drugs may be required.

Epileptic seizures can be provoked by several factors. Better understanding of these factors may improve a patient's sense of control and could reduce seizures. In daily practice, the recognition of seizure precipitants relies heavily on clinical or video-EEG evidence, which can be difficult to obtain. Studies of seizure provocation are largely based on selected hospital-based patient populations, which may lead to biased occurrence estimates. Self-reported seizure precipitants are rarely studied, yet are necessary to understand the experiences of patients and improve epilepsy management. We performed a cross-sectional community-based study of 248 epilepsy patients, selected by pharmacy records of anti-epileptic drug use. Self-reported seizure precipitants and potential associated characteristics were assessed using questionnaires. Almost half of all patients (47 %) reported one or more seizure precipitants, of which stress, sleep deprivation, and flickering lights were the most common. In this community-based setting, light-provoked seizures were especially frequent compared to the literature. Idiopathic generalized epilepsy (IGE), a lower age at seizure onset, and having auras or prodromes were found to be important independent prognostic factors associated with provoked seizures. IGE and a younger age at seizure onset have been linked to provoked seizures in earlier reports. The finding of auras or prodromes as a prognostic factor was unexpected, though case reports have described provoked seizures in patients having auras. Assessment of these factors may facilitate the early recognition of seizure precipitants in daily clinical practice. This is important for the optimization of epilepsy management for a large group of patients, as provoked seizures are expected to occur frequently.

We identified 15q13.3 microdeletions encompassing the CHRNA7 gene in 12 of 1,223 individuals with idiopathic generalized epilepsy (IGE), which were not detected in 3,699 controls (joint P = 5.32 x 10(-8)). Most deletion carriers showed common IGE syndromes without other features previously associated with 15q13.3 microdeletions, such as intellectual disability, autism or schizophrenia. Our results indicate that 15q13.3 microdeletions constitute the most prevalent risk factor for common epilepsies identified to date.

A 31-year-old man presented with a 3-month history of progressive dysarthria and 1 month of gradually worsening motor seizures predominantly affecting the right face. Examination was unremarkable except for a mild spastic dysarthria and slow, alternating tongue movements, probably due to a partial opercular syndrome. Seizures captured during EEG recording showed a jacksonian march starting over the opercular aspect of the motor homunculus,1,2 and anarthria and sialorrhea without EEG correlate (videos 1 and 2 on the Neurology ® Web site at Neurology.org and figure 1). MRI brain showed a left opercular tumor (figure 2, A and B), found to be an anaplastic astrocytoma after resection. The patient has been seizure free for 12 months after treatment with carbamazepine and resective surgery but has residual dysarthria.

A genetic contribution to a broad range of epilepsies has been postulated, and particularly copy number variations (CNVs) have emerged as significant genetic risk factors. However, the role of CNVs in patients with epilepsies with complex phenotypes is not known. Therefore, we investigated the role of CNVs in patients with unclassified epilepsies and complex phenotypes. A total of 222 patients from three European countries, including patients with structural lesions on magnetic resonance imaging (MRI), dysmorphic features, and multiple congenital anomalies, were clinically evaluated and screened for CNVs. MRI findings including acquired or developmental lesions and patient characteristics were subdivided and analyzed in subgroups. MRI data were available for 88.3% of patients, of whom 41.6% had abnormal MRI findings. Eighty-eight rare CNVs were discovered in 71 out of 222 patients (31.9%). Segregation of all identified variants could be assessed in 42 patients, 11 of which were de novo. The frequency of all structural variants and de novo variants was not statistically different between patients with or without MRI abnormalities or MRI subcategories. Patients with dysmorphic features were more likely to carry a rare CNV. Genome-wide screening methods for rare CNVs may provide clues for the genetic etiology in patients with a broader range of epilepsies than previously anticipated, including in patients with various brain anomalies detectable by MRI. Performing genome-wide screens for rare CNVs can be a valuable contribution to the routine diagnostic workup in patients with a broad range of childhood epilepsies.

Dorothee G.A. Kasteleijn-Nolst Trenite *, Linda Volkers , Eric Strengman , Herman M. Schippers , Willem Perquin , Gerrit-Jan de Haan , Anastasia O. Gkountidi , Ruben van’t Slot , Stan F. van de Graaf , Bosanka Jocic-Jakubi , Giuseppe Capovilla , Athanasios Covanis , Pasquale Parisi , Pierangelo Veggiotti , Mario Brinciotti , Gemma Incorpora , Marta Piccioli , Laura Cantonetti , Samuel F. Berkovic , Ingrid E. Scheffer , Eva H. Brilstra , Anja C.M. Sonsma , Adri J. Bader , Carolien G.F. de Kovel , Bobby P.C. Koeleman a

To explore the relationship of peripapillary retinal nerve fiber layer (ppRNFL) thinning in individuals exposed to the antiepileptic drug vigabatrin with respect to 2 separate variables: cumulative vigabatrin exposure and severity of vigabatrin-associated visual field loss (VAVFL).Cross-sectional observational study.Subjects were older than 18 years, 129 with vigabatrin-treated epilepsy (vigabatrin-exposed group) and 87 individuals with epilepsy never treated with vigabatrin (nonexposed group).All subjects underwent ppRNFL imaging using spectral-domain optical coherence tomography. Eighty-four vigabatrin-exposed individuals underwent Goldmann kinetic perimetry. The visual field examined from the right eye was categorized as normal (n = 47), mildly abnormal (n = 18), or moderately to severely abnormal (n = 19). In 91 vigabatrin-exposed individuals, the cumulative vigabatrin exposure could be ascertained: 41 subjects received 1000 g or less, 23 subjects received more than 1000 g but equal to or less than 2500 g, 16 subjects received more than 2500 g but equal to or less than 5000 g or less, and 11 subjects received more than 5000 g.Differences in ppRNFL thickness across the twelve 30° sectors: (1) among all nonexposed individuals and all vigabatrin-exposed individuals, (2) between each vigabatrin-exposed group, according to cumulative vigabatrin exposure, and the nonexposed group, (3) among different vigabatrin-exposed subjects grouped according to cumulative vigabatrin exposure, and (4) among vigabatrin-exposed subjects grouped according to severity of VAVFL.The ppRNFL was significantly thinner in vigabatrin-exposed compared with nonexposed individuals in most 30° sectors (P0.004). The temporal, temporal superior, and temporal inferior 30° sectors, as well as the nasal 30° sector, were not affected. There was a trend for increasing ppRNFL thinning with increasing cumulative vigabatrin exposure. The nasal-superior 30° sector was significantly thinner in group 1 (≤1000 g) compared with nonexposed individuals (P0.05) and in vigabatrin-exposed individuals with normal visual fields compared with nonexposed individuals (P0.05).After vigabatrin exposure in individuals receiving cumulative doses of 1000 g or less or in the presence of normal visual fields, ppRNFL thinning in the nasal superior 30° sector may occur. With higher cumulative doses of vigabatrin exposure, additional ppRNFL thinning was observed. The temporal aspects of the ppRNFL are spared, even in individuals with large cumulative vigabatrin exposures and moderate or severe VAVFL.

Little is known about pregnancy-induced alterations in the pharmacokinetics of the newer antiepileptic drugs, especially when used in combinations. Two women receiving combination therapy of lamotrigine (LTG) and oxcarbazepine (OXC) were followed prospectively during pregnancy and puerperium. Steady-state concentrations of LTG and the active metabolite of OXC, 10-hydroxycarbazepine (MHD), were measured at regular intervals using a dried blood spot method, and clearances were calculated. A strong effect of pregnancy on the clearance of both LTG and MHD was seen. An increase in seizure frequency occurred in both women. This stresses the importance of therapeutic drug monitoring of LTG and MHD during pregnancy. In case of breakthrough seizures or increased seizure frequency, dosage adjustment of both drugs may be required.

Rectal diazepam is established as a standard rescue or emergency treatment for seizure or status epilepticus; however, the rectal route of administration has not been universally accepted. To determine if an alternative route of administration of a benzodiazepine was equally effective, we compared a novel midazolam HCl concentrated nasal spray (MDZ-n) with diazepam rectal solution (DZP-r) in the treatment of prolonged seizures in a residential epilepsy center. In 21 adult patients with medically refractory epilepsy, 124 seizure-exacerbations were treated by their caregivers, alternatively with 10 mg DZP-r and 10 mg concentrated MDZ-n, two or three treatments with each medication for each patient. No difference was demonstrated in efficacy or time to effect between the two drugs. Common treatment emerging adverse effects were drowsiness for both drugs in more than 50% of the administrations, and short-lasting local irritation after 29% of MDZ-n. No severe adverse events occurred. The nasal spray was preferred to the rectal solution by 16 of 21 caregivers and patients conjointly. MDZ-n was equal to DZP-r with respect to efficacy and side effects in the suppression of seizure exacerbations. The majority of patients and caregivers preferred the nasal spray over the rectal formulation.

Summary: Purpose: The EFHC1 gene, encoding a protein with a Ca2+-sensing EF-hand motif, is localized at 6p12 and was recently reported as mutated in six Mexican juvenile myoclonic epilepsy (JME) families linked to this region. We had previously confirmed linkage between JME and 6p11-12 in 18 Dutch families, and shown exclusionary lod scores at 6p21.3. We therefore evaluated the relevance of EFHC1 in our set of 6p11-12–linked families. Methods: We screened all coding and regulatory regions of EFHC1 by direct sequencing, and the detected variants were tested in a case–control association study. Results: We found none of the five mutations previously reported in the Mexican families, but identified nine variants, three of which are novel: 5′ upstream region (c.-146_147delGC), nonsynonymous (R159W, R182H, M448T, I619L), intronic (IVS3 + 10A>G, IVS8 + 175_176delTT, IVS10 + 59C>T), and 3′ UTR (c.+121C>A). These variants did not cosegregate with JME and did not account for the observed linkage at the 6p11-12 locus. Furthermore, no significant association was detected between JME and these variants in 112 unrelated patients and 180 controls. Finally, none of the mutations reported in Mexican families was found in 100 unrelated patients. Conclusions: We found no evidence that EFHC1 is a major genetic risk factor for JME susceptibility in Dutch patients. The EFHC1 variants reported in Mexican families may be mendelian variants specific for those families, suggesting that for Dutch patients and possibly many other populations, the main disease variant at the 6p11-12 is yet to be identified.

Summary: Purpose: A large multigenerational family with benign familial neonatal convulsions (BFNC) was revisited to identify the disease-causing mutation and to assess long-term outcome. Methods: We supplemented the original data with recent clinical and neurophysiologic data on patients and first-degree relatives, including information on seizure recurrence. We conducted linkage analysis at the EBN1 and EBN2 loci, followed by mutation analysis of KCNQ2. We evaluated the qualitative effect of the KCNQ2 mutation at the messenger RNA (mRNA) level by using reverse-transcribed total RNA isolated from leukocytes. Results: Thirteen relatives had a history of neonatal convulsions, 11 of whom showed remission within 2 months. One patient showed an atypical course of neonatal convulsions, developing photosensitive myoclonic epilepsy at age 13 years. We found suggestive linkage of the BFNC phenotype to the 20q13-EBN1 locus (lod score, 2.03) and an intronic mutation IVS14-6 C>A in KCNQ2 segregating with the trait in all affected members, but absent in 100 unrelated control subjects. This mutation creates a new, preferentially used, splice site. Alternative splicing adds 4 nt containing a premature stop codon to the transcript, resulting in a truncated protein after position R588. Conclusions: We detected and characterized a novel splicing mutation in the brain-specific KCNQ2 gene by using easily accessible blood leukocytes. Aberrant splicing cosegregates with BFNC but not with photosensitivity.

Summary: Purpose: The interaction of genetic predisposition and the environment in the development of epilepsy is often discussed, but, aside from some animal reflex epilepsies, little evidence supports such interaction in the development of reflex epilepsy in humans. Methods: We describe the history of a 16-year-old boy in whom photosensitive epilepsy developed after a period of weekly exposures to high-intensity light flashes. Results: Both he and his clinically unaffected monozygotic twin were found to be photosensitive. Conclusions: This case report suggests that some genetic forms of human reflex epilepsy may be elicited by repeated environmental exposure to the appropriate stimulus, similar to some of the stimulus-induced epilepsies seen in animals.

The interplay of multiple genetic factors, as opposed to monogenic inheritance, is suspected to play a role in many idiopathic generalized epilepsies. This leads to a digenic or oligogenic inheritance model, which although rather simplified, may explain at least some of the clinical observations. Here we describe a family in which the clinical phenotype in the offspring can be explained by a combination of photosensitivity and epilepsy traits that segregated independently of each other. This case history demonstrates the need to evaluate family histories in more detail in order to uncover potential clinical markers for genetic factors in complex epilepsies.

Photoparoxysmal response (PPR) is an abnormal visual sensitivity of the brain in reaction to intermittent photic stimulation. It is an epilepsy-related electroencephalographic trait with high prevalence in idiopathic epilepsies, especially in common idiopathic generalized epilepsies (IGEs), such as childhood absence epilepsy and juvenile myoclonic epilepsy. This degree of co-morbidity suggests that PPR may be involved in the predisposition to IGE. The identification of genes for PPR would, therefore, aid the dissection of the genetic basis of IGE. Sixteen PPR-multiplex families were collected to conduct a genome-wide linkage scan using broad (all PPR types) and narrow (exclusion of PPR types I and II and the occipital epilepsy cases) models of affectedness for PPR. We found an empirical genome-wide significance for parametric (HLOD) and non-parametric (NPL) linkage (Pgw(HLOD)=0.004 and Pgw(NPL)=0.01) for two respective chromosomal regions, 7q32 at D7S1804 (HLOD=3.47 with alpha=1, P(NPL)=3.39x10(-5)) and 16p13 at D16S3395 (HLOD=2.44 with alpha=1, P(NPL)=7.91x10(-5)). These two genomic regions contain genes that are important for the neuromodulation of cortical dynamics and may represent good targets for candidate-gene studies. Our study identified two susceptibility loci for PPR, which may be related to the underlying myoclonic epilepsy phenotype present in the families studied.

Loss-of-function mutations in the cystatin B (CSTB), a cysteine protease inhibitor, gene underlie progressive myoclonus epilepsy of Unverricht–Lundborg type (EPM1), characterized by myoclonic and tonic–clonic seizures, ataxia and a progressive course. A minisatellite repeat expansion in the promoter region of the CSTB gene is the most common mutation in EPM1 patients and leads to reduced mRNA levels. Seven other mutations altering the structure of CSTB, or predicting altered splicing, have been described. Using a novel monoclonal CSTB antibody and organelle-specific markers in human primary myoblasts, we show here that endogenous CSTB localizes not only to the nucleus and cytoplasm but also associates with lysosomes. Upon differentiation to myotubes, CSTB becomes excluded from the nucleus and lysosomes, suggesting that the subcellular distribution of CSTB is dependent on the differentiation status of the cell. Four patient mutations altering the CSTB polypeptide were transiently expressed in BHK-21 cells. The p.Lys73fsX2-truncated mutant protein shows diffuse cytoplasmic and nuclear distribution, whereas p.Arg68X is rapidly degraded. Two missense mutations, the previously described p.Gly4Arg affecting the highly conserved glycine, critical for cathepsin binding, and a novel mutation, p.Gln71Pro, fail to associate with lysosomes. These data imply an important lysosome-associated physiological function for CSTB and suggest that loss of this association contributes to the molecular pathogenesis of EPM1.

Summary: Purpose: Previous linkage studies provided evidence for juvenile myoclonic epilepsy (JME) susceptibility loci at 6p11-12, HLA-6p21.3 region, 15q14, and 5q34. These results indicate locus heterogeneity or interpopulation differences, thus underlining the importance of replication studies. Methods: We describe a replication linkage study of the 6p-q13 region in 18 families ascertained from JME probands of Dutch descent. In the presence of heterogeneity, the definition of the disease status may be crucial, and we therefore used two disease phenotypes: narrow [JME/idiopathic generalized epilepsy (IGE)-“only”] and broad (JME/IGE-plus-fast EEG background activity). Results: We found evidence of linkage at 6p11-12 in multipoint analyses (p < 0.01 in a replication study) for both these disease definitions. Analysis of this region, assuming heterogeneity and autosomal dominant inheritance with a conservative 60% of penetrance, gave a maximum multipoint parametric lod score of 2.07 at D6S1573 for the narrow phenotype and peaked at 2.53 between D6S1623 and D6S1573 for the broad phenotype. The p value for nonparametric linkage reached 0.0013 for the narrow phenotype and 0.0010 for the broad. Significant exclusion (lod score ≤2) was found for the HLA region and for 10 to 30 cM telomeric to HLA. Our results provide evidence for a susceptibility locus for JME/IGE-plus-fast EEG background activity at 6p11-12. Conclusions: Additionally, by using a narrow definition, we were able to confirm previous evidence for a JME–IGE locus at this location.

Purpose: Univerricht-Lundborg disease (ULD), with its major symptom of action myoclonus, is supposed to be very rare in the Netherlands and western Europe. We hypothesized that the syndrome may be underdiagnosed in patients with myoclonus epilepsy. Methods: Mutation analysis of the cystatin B gene was performed in 21 cases with uncontrolled myoclonus. Results: Seven of the 21 evaluated cases carried mutations in the cystatin B gene. Diagnosis of ULD was made with a mean delay of 20 years from symptom onset. Conclusions: This study from a country without previous reports of ULD suggests that underdiagnosis of the syndrome is likely. These findings also indicate that persons with juvenile-onset myoclonus epilepsy with action myoclonus should be analyzed for ULD.

Summary: Purpose: To report a new form of reflex epilepsy in which the seizures are repeatedly and exclusively triggered by answering the telephone. Methods: Three patients with a history of telephone-induced seizures were studied in detail by means of clinical, EEG, and neuroradiologic investigations. Intensive video-EEG monitoring to record the reflex seizures also was performed in all cases. Results: The patients (two men, one woman, aged 21 to 30 years) had the onset during early adulthood of complex partial and secondarily generalized seizures exclusively triggered by answering the telephone. The seizures were stereotyped, with subjective auditory or vertiginous auras and inability to speak or understand the spoken voices. In one patient, a telephone-induced seizure arising from the dominant temporal lobe was recorded by means of video-EEG technique. In the interictal EEGs, temporal abnormalities were detected in all cases. The patients had a normal neurologic examination and normal magnetic resonance imaging or computed tomography scans. Conclusions: We suggest that telephone epilepsy is a previously unrecognized form of reflex epilepsy induced by a complex auditory stimulus involving the lateral temporal areas.

A recent genome-wide scan showed strong evidence for a major locus for common syndromes of idiopathic generalized epilepsy (IGE) at the marker D18S474 on chromosome 18q21.1 (LOD score 4.5/5.2 multipoint/two-point). The present replication study tested the presence of an IGE locus in the chromosomal region 18q21.1. Our linkage study included 130 multiplex families of probands with common IGE syndromes. Eleven microsatellite polymorphisms encompassing a candidate region of 30 cM on either side of the marker D18S474 were genotyped. The two-point homogeneity LOD score for D18S474 showed strong evidence against linkage at the original linkage peak (Z = -18.86 at theta(m = f) = 0.05), assuming a recessive mode of inheritance with 50% penetrance. Multipoint parametric heterogeneity LOD scores-2 were obtained along the candidate region when proportions of linked families greater than 35% were assumed under recessive inheritance. Furthermore, non-parametric multipoint linkage analyses showed no hint of linkage throughout the candidate region (P0.19). Accordingly, we failed to support evidence for a major IGE locus in the chromosomal region 18p11-18q23. If there is a susceptibility locus for IGE in this region then the size of the effect or the proportion of linked families is too small to detect linkage in the investigated family sample.

Genetic factors play a major role in the aetiology of idiopathic generalised epilepsies (IGEs). The present genome scan was designed to identify susceptibility loci that predispose to a spectrum of common IGE syndromes. Our collaborative study included 130 IGE-multiplex families ascertained through a proband with either an idiopathic absence epilepsy or juvenile myoclonic epilepsy, and one or more siblings affected by an IGE trait. In total, 413 microsatellite polymorphisms were genotyped in 617 family members. Non-parametric multipoint linkage analysis, using the GeneHunter program, provided significant evidence for a novel IGE susceptibility locus on chromosome 3q26 (Z(NPL) = 4.19 at D3S3725; P = 0.000017) and suggestive evidence for two IGE loci on chromosome 14q23 (Z(NPL) = 3.28 at D14S63; P = 0.000566), and chromosome 2q36 (Z(NPL) = 2.98 at D2S1371; P = 0.000535). The present linkage findings provide suggestive evidence that at least three genetic factors confer susceptibility to generalised seizures in a broad spectrum of IGE syndromes. The chromosomal segments identified harbour several genes involved in the regulation of neuronal ion influx which are plausible candidates for mutation screening.