Papers by Gerrit-Jan de Haan
Frontiers in Neuroscience
BackgroundThe anti-seizure medication vigabatrin (VGB) is effective for controlling seizures, esp... more BackgroundThe anti-seizure medication vigabatrin (VGB) is effective for controlling seizures, especially infantile spasms. However, use is limited by VGB-associated visual field loss (VAVFL). The mechanisms by which VGB causes VAVFL remains unknown. Average peripapillary retinal nerve fibre layer (ppRNFL) thickness correlates with the degree of visual field loss (measured by mean radial degrees). Duration of VGB exposure, maximum daily VGB dose, and male sex are associated with ppRNFL thinning. Here we test the hypothesis that common genetic variation is a predictor of ppRNFL thinning in VGB exposed individuals. Identifying pharmacogenomic predictors of ppRNFL thinning in VGB exposed individuals could potentially enable safe prescribing of VGB and broader use of a highly effective drug.MethodsOptical coherence topography (OCT) and GWAS data were processed from VGB-exposed individuals (n = 71) recruited through the EpiPGX Consortium. We conducted quantitative GWAS analyses for the fo...
Genetics of Epilepsy, a Dutch Cohort Study
Clinical and genetic complexities of the generalized myoclonus epilepsies
[From gene to disease; progressive myoclonus epilepsy of Unverricht-Lundborg and mutations in the cystatin B gene]
PubMed, May 4, 2002
Progressive myoclonus epilepsy type 1 of Unverricht-Lundborg (EPM1) is a rare disorder, associate... more Progressive myoclonus epilepsy type 1 of Unverricht-Lundborg (EPM1) is a rare disorder, associated with mutations in the cystatin B (CSTB) gene. The most prevalent molecular abnormality is an expansion of a dodecamer repeat in the promoter region of the CSTB gene, but point mutations in the CSTB gene have also been found. DNA examination may be useful in discriminating EPM1 from juvenile myoclonic epilepsy, and from other types of progressive myoclonus epilepsy. An early diagnosis is important to optimise treatment and to provide an adequate prognosis and prediction of recurrence.
British Journal of Clinical Pharmacology, May 1, 2002
Aims To investigate the pharmacokinetic and pharmacodynamic profile of midazolam administered as ... more Aims To investigate the pharmacokinetic and pharmacodynamic profile of midazolam administered as a concentrated intranasal spray, compared with intravenous midazolam, in healthy adult subjects. Methods Subjects were administered single doses of 5 mg midazolam intranasally and intravenously in a cross-over design with washout period of 1 week. The total plasma concentrations of midazolam and the metabolite 1-hydroxymidazolam after both intranasal and intravenous administration were described with a single pharmacokinetic model. b-band EEG activity was recorded and related to midazolam plasma concentrations using an exponential pharmacokinetic/pharmacodynamic model. Results Administration of the intranasal spray led to some degree of temporary irritation in all six subjects, who nevertheless found intranasal administration acceptable and not painful. The mean (ts.d.) peak plasma concentration of midazolam of 71 (t25 ng ml x1) was reached after 14 (t5 min). Mean bioavailability following intranasal administration was 0.83t0.19. After intravenous and intranasal administration, the pharmacokinetic estimates of midazolam were: mean volume of distribution at steady state 1.11t0.25 l kg x1 , mean systemic clearance 16.1t4.1 ml min x1 kg x1 and harmonic mean initial and terminal half lives 8.4t2.4 and 79t30 min, respectively. Formation of the 1-hydroxymetabolite after intranasal administration did not exceed that after intravenous administration. Conclusions In this study in healthy volunteers a concentrated midazolam nasal spray was easily administered and well tolerated. No serious complications of the mode of administration or the drug itself were reported. Rapid uptake and high bioavailability were demonstrated. The potential of midazolam given via a nasal spray in the acute treatment of status epilepticus and other seizure disruptions should be evaluated.
Sudden Cardiac Arrest in Epilepsy : Circumstances and Risk Factors
Epilepsia, Jun 1, 2013
Paroxysmal Cerebral Disorder
European Journal of Human Genetics, Jan 20, 2005
Successful treatment of acute subdural haematoma associated with severe bleeding disorder
Journal of Neurology, 1987
A 76-year-old man suffering from myelofibrosis with thrombocytopenia sustained an acute subdural ... more A 76-year-old man suffering from myelofibrosis with thrombocytopenia sustained an acute subdural haematoma with severe neurological deficit. He was treated initially by bedrest and dexamethasone. Craniotomy was contraindicated because his bleeding time exceeded 20 min in spite of multiple infusions of platelet concentrate. After 3 weeks his condition deteriorated with increase of the fluid collection shown by CT. Partial drainage of the haematoma by subdural puncture with a 22-gauge spinal needle resulted in complete recovery from the neurological deficit and complete resorption of the effusion. The case shows that it is possible to avoid craniotomy in the acute phase of a subdural haematoma in patients with bleeding disorders and that it may be advantageous to use needle evacuation instead of burr-hole drainage in the chronic phase.
Unusual combination of epilepsy phenotypes and a SCNM1 mutation in a three-generational family: photosensitivity, persistent at high age, and talking induced myoclonic jaw- jerks
We analysed the clinical phenotypes, evolution, and genetics of a large family presented through ... more We analysed the clinical phenotypes, evolution, and genetics of a large family presented through a single proband who suffered increasingly from jerks in her jaw especially when speaking in front of the classroom and who appeared to be photosensitive, both clinically and in EEG recordings. The proband was then investigated by Whole Exome Sequencing, which identified 4 novel, predicted damaging mutations in different genes, all located in one of the four linkage peaks. An Arg267Cys mutation in the SCNM1 gene was carried in heterozygous state in all photosensitive family members. The gene regulates splicing of voltage gated ion channels and the mutation indeed affected the level of splicing of the SCN1A splice variant that was also carried by 7 of the affected family members. No other SCNM1 mutations were found in unrelated PPR European patients, suggesting that SCNM1 is a private mutation of this family and may be causing this unique combination of phenotypes
Epilepsy & Behavior, 2007
Generic substitution is encouraged as a cost containment strategy for the management of health ca... more Generic substitution is encouraged as a cost containment strategy for the management of health care resources. However, in epilepsy, the consequences of loss of symptom control are important, and antiepileptic drugs have narrow therapeutic indices. For this reason, generic substitution may be problematic, and certain health authorities have excluded antiepileptic drugs from overall policy recommendations on generic prescribing. The absence of bioequivalence data among generic forms and the relatively broad criteria for bioequivalence with the branded drug allow differences in drug exposure to arise that may be clinically relevant and necessitate monitoring of plasma levels when switching formulations to avoid loss of seizure control or emergence of side effects. Management of these issues carries a significant cost, which should be weighed carefully against the cost savings acquired when purchasing the drug. Both physicians and patients have a right to be informed and approve before pharmacists make a generic substitution or switch between generics.
Epilepsia, 2000
Such cognitive effects have been claimed for most of the antiepileptic drugs (AEDs), although the... more Such cognitive effects have been claimed for most of the antiepileptic drugs (AEDs), although the clinical rel
Epilepsy & Behavior, Jul 1, 2013
Autosomal dominant lateral temporal lobe epilepsy (ADLTE) is characterized by focal seizures with... more Autosomal dominant lateral temporal lobe epilepsy (ADLTE) is characterized by focal seizures with auditory features or aphasia. Mutations in the leucine-rich glioma-inactivated 1 (LGI1) gene have been reported in up to 50% of families with ADLTE. Attention-deficit/hyperactivity disorder (ADHD) symptoms have not yet been reported in these families. Clinical data were collected from a family with five affected members. Leucinerich glioma-inactivated 1 exons and boundaries were sequenced by standard methods. Attention-deficit/ hyperactivity disorder symptoms were scored based on the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) criteria. Affected members had seizures with auditory features and psychic auras, and some experienced nightmares. A heterozygous c.431+1G>A substitution in LGI1 was detected in all members. Significantly more hyperactivity symptoms were found in family members carrying the LGI1 mutation. This study expands the phenotypic spectrum associated with ADLTE due to LGI1 mutation and underlines the need for more systematic evaluation of ADHD and related symptoms.
Seizure-european Journal of Epilepsy, Dec 1, 2015
Dorothé e G.
Acta neurologica Scandinavica, Jan 14, 2018
To assess effectiveness and tolerability of first-line and conversion to lacosamide monotherapy f... more To assess effectiveness and tolerability of first-line and conversion to lacosamide monotherapy for focal seizures. Retrospective, non-interventional chart review of lacosamide monotherapy patients aged ≥16 years in Europe. Outcomes included retention rate at observational point (OP) 3 (12 ± 3 months), seizure freedom rates at OP2 (6 ± 3 months) and OP3 and adverse drug reactions (ADRs). A total of 439 patients were included (98 first-line and 341 conversion to monotherapy; 128 aged ≥65 years [25 first-line and 103 conversion to monotherapy]). First-line and conversion to monotherapy retention rates were 60.2% (59/98; 95% confidence interval [CI] 49.8%-70.0%) and 62.5% (213/341; 57.1%-67.6%), respectively. Kaplan-Meier estimates of 12-month retention rates were 81.2% and 91.4% for first-line and conversion to monotherapy, respectively. First-line and conversion to monotherapy retention rates in patients aged ≥65 years were 60.0% (38.7%-78.9%) and 68.9% (59.1%-77.7%), respectively. A...
Background The epilepsies are a clinically heterogeneous group of neurological disorders. Despite... more Background The epilepsies are a clinically heterogeneous group of neurological disorders. Despite strong evidence for heritability, genome-wide association studies have had little success in identifi cation of risk loci associated with epilepsy, probably because of relatively small sample sizes and insuffi cient power. We aimed to identify risk loci through meta-analyses of genome-wide association studies for all epilepsy and the two largest clinical subtypes (genetic generalised epilepsy and focal epilepsy). Methods We combined genome-wide association data from 12 cohorts of individuals with epilepsy and controls from population-based datasets. Controls were ethnically matched with cases. We phenotyped individuals with epilepsy into categories of genetic generalised epilepsy, focal epilepsy, or unclassifi ed epilepsy. After standardised fi ltering for quality control and imputation to account for diff erent genotyping platforms across sites, investigators at each site conducted a linear mixed-model association analysis for each dataset. Combining summary statistics, we conducted fi xed-eff ects meta-analyses of all epilepsy, focal epilepsy, and genetic generalised epilepsy. We set the genome-wide signifi cance threshold at p<1•66 × 10-⁸. Findings We included 8696 cases and 26 157 controls in our analysis. Meta-analysis of the all-epilepsy cohort identifi ed loci at 2q24.3 (p=8•71 × 10-¹⁰), implicating SCN1A, and at 4p15.1 (p=5•44 × 10-⁹), harbouring PCDH7, which encodes a protocadherin molecule not previously implicated in epilepsy. For the cohort of genetic generalised epilepsy, we noted a single signal at 2p16.1 (p=9•99 × 10-⁹), implicating VRK2 or FANCL. No single nucleotide polymorphism achieved genome-wide signifi cance for focal epilepsy. Interpretation This meta-analysis describes a new locus not previously implicated in epilepsy and provides further evidence about the genetic architecture of these disorders, with the ultimate aim of assisting in disease classifi cation and prognosis. The data suggest that specifi c loci can act pleiotropically raising risk for epilepsy broadly, or can have eff ects limited to a specifi c epilepsy subtype. Future genetic analyses might benefi t from both lumping (ie, grouping of epilepsy types together) or splitting (ie, analysis of specifi c clinical subtypes). Funding International League Against Epilepsy and multiple governmental and philanthropic agencies.
Optical Coherence Tomography in Vigabatrin-Exposed Patients: Exploring the Structure-Function Relationship
Investigative Ophthalmology & Visual Science, Apr 17, 2010
Journal of International Relations and Development, 2006
The quality of articles the editors accept for publications in the Journal of International Relat... more The quality of articles the editors accept for publications in the Journal of International Relations and Development depends on the valuable suggestions from colleagues who serve as external reviewers. The editors gratefully acknowledge the service of the following colleagues who provided reviews during the preparation of volume 9:
Epilepsie, periodiek voor professionals
Op 19 december 2022 vond in Utrecht de promotie plaats van Bianca Berghuis, op een proefschrift g... more Op 19 december 2022 vond in Utrecht de promotie plaats van Bianca Berghuis, op een proefschrift getiteld: Carbamazepine en Oxcarbazepine Induced Hyponatremia.
Genome-wide linkage scan of epilepsy-related photoparoxysmal EEG response: evidence
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Papers by Gerrit-Jan de Haan