SMART syndrome: a late reversible complication after radiation therapy for brain tumours

With intensified treatment leading to longer survival, complications of therapy for brain tumours are more frequently observed. Regarding radiation therapy, progressive and irreversible white matter disease with cognitive decline is most feared. We report on four patients with reversible clinical and radiological features occurring years after radiation for brain tumours, suggestive for the so called SMART syndrome (stroke-like migraine attacks after radiation therapy). All four patients (males, age 36–60 years) had been treated with focal brain radiation for a primary brain tumour or with whole-brain radiation therapy for brain metastases. Ranging from 2 to 10 years following radiation therapy patients presented with headache and focal neurological deficits, suggestive for tumour recurrence. Two patients also presented with focal seizures. MRI demonstrated typical cortical swelling and contrast enhancement, primarily in the parieto-occipital region. On follow-up both clinical and MRI features improved spontaneously. Three patients eventually proved to have tumour recurrence. The clinical and radiological picture of these patients is compatible with the SMART syndrome, a rare complication of radiation therapy which is probably under recognized in brain tumour patients. The pathophysiology of the SMART syndrome is poorly understood but bears similarities with the posterior reversible encephalopathy syndrome (PRES). These four cases underline that the SMART syndrome should be considered in patients formerly treated with radiation therapy for brain tumours, who present with new neurologic deficits. Before the diagnosis of SMART syndrome can be established other causes, such as local tumour recurrence, leptomeningeal disease or ischemic disease should be ruled out

Comparative effectiveness of antiepileptic drugs in juvenile myoclonic epilepsy

Abstract Objective To study the effectiveness and tolerability of antiepileptic drugs (AEDs) commonly used in juvenile myoclonic epilepsy (JME). Methods People with JME were identified from a large database of individuals with epilepsy, which includes detailed retrospective information on AED use. We assessed secular changes in AED use and calculated rates of response (12-month seizure freedom) and adverse drug reactions (ADRs) for the five most common AEDs. Retention was modeled with a Cox proportional hazards model. We compared valproate use between males and females. Results We included 305 people with 688 AED trials of valproate, lamotrigine, levetiracetam, carbamazepine, and topiramate. Valproate and carbamazepine were most often prescribed as the first AED. The response rate to valproate was highest among the five AEDs (42.7\%), and significantly higher than response rates for lamotrigine, carbamazepine, and topiramate; the difference to the response rate to levetiracetam (37.1\%) was not significant. The rates of ADRs were highest for topiramate (45.5\%) and valproate (37.5\%). Commonest ADRs included weight change, lethargy, and tremor. In the Cox proportional hazards model, later start year (1.10 [1.08-1.13], P < 0.001) and female sex (1.41 [1.07-1.85], P = 0.02) were associated with shorter trial duration. Valproate was associated with the longest treatment duration; trials with carbamazepine and topiramate were significantly shorter (HR [CI]: 3.29 [2.15-5.02], P < 0.001 and 1.93 [1.31-2.86], P < 0.001). The relative frequency of valproate trials shows a decreasing trend since 2003 while there is an increasing trend for levetiracetam. Fewer females than males received valproate (76.2 vs 92.6\%, P = 0.001). Significance In people with JME, valproate is an effective AED; levetiracetam emerged as an alternative. Valproate is now contraindicated in women of childbearing potential without special precautions. With appropriate selection and safeguards in place, valproate should remain available as a therapy, including as an alternative for women of childbearing potential whose seizures are resistant to other treatments

Analysis of shared common genetic risk between amyotrophic lateral sclerosis and epilepsy

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

GWAS meta-analysis of over 29,000 people with epilepsy identifies 26 risk loci and subtype-specific genetic architecture

Epilepsy is a highly heritable disorder affecting over 50 million people worldwide, of which about one-third are resistant to current treatments. Here we report a multi-ancestry genome-wide association study including 29,944 cases, stratified into three broad categories and seven subtypes of epilepsy, and 52,538 controls. We identify 26 genome-wide significant loci, 19 of which are specific to genetic generalized epilepsy (GGE). We implicate 29 likely causal genes underlying these 26 loci. SNP-based heritability analyses show that common variants explain between 39.6% and 90% of genetic risk for GGE and its subtypes. Subtype analysis revealed markedly different genetic architectures between focal and generalized epilepsies. Gene-set analyses of GGE signals implicate synaptic processes in both excitatory and inhibitory neurons in the brain. Prioritized candidate genes overlap with monogenic epilepsy genes and with targets of current antiseizure medications. Finally, we leverage our results to identify alternate drugs with predicted efficacy if repurposed for epilepsy treatment

Carbamazepine and oxcarbazepine induced hyponatremia

Epilepsy affects about 1 % of people and is mainly treated with anti-seizure medication (ASM). The use of carbamazepine (CBZ) and oxcarbazepine (OXC) as first-line ASM in treating focal epilepsy is limited by hyponatremia. This thesis describes the association between CBZ or OXC and hyponatremia and the clinical impact that carbamazepine- and oxcarbazepine-induced hyponatremia (COIH) has on people with epilepsy. We assessed the occurrence of COIH in a large cohort of people with epilepsy and looked for possible determinants. Over 2,600 people were included from our tertiary epilepsy centre in the Netherlands, and we collected data on sodium level measurements in people who (had) used CBZ and OXC. Our main finding was that hyponatremia (Na+ ≤134 mmol/L) occurred in about a quarter of those taking CBZ and almost half of those taking OXC, in line with other studies. Severe hyponatremia (Na+ ≤128 mmol/L) occurred in 7% in the CBZ group and 22% in the OXC group. Age over 40 years, high serum levels of CBZ and OXC and concomitant use of other ASMs were the main risk factors for hyponatremia in both treatment groups. Females on OXC were at a higher risk of hyponatremia than males. Symptoms present at hyponatremia, which could not be explained by another clear cause such as overt ASM intoxication or comorbidity were scored and found in almost half of people who had COIH. They lead to hospital admissions in 3%, primarily because of falls. Next we assessed the AEs experienced by people taking CBZ or OXC and whether they could be attributed to COIH. We performed an observational retrospective study collecting data between 2017 and 2019 on serum sodium levels and AEs in 410 people with COIH and 300 with normal sodium levels from our previously described cohort. Our main finding was the occurrence of AEs in 65% of people with hyponatremia compared to 21% with normal sodium levels (OR 7,5, p=<0,001) and in 83% of people with severe hyponatremia compared to 55% in those with mild hyponatremia (p=<0,001). Significant predictors of AEs were the drug (OXC vs CBZ), and the number of concomitant ASMs. Dizziness, tiredness, instability and diplopia were reported more often in the hyponatremia group than in those with normal levels. Finally we searched for genetic factors contributing to COIH. In 1,141individuals of a CBZ/OXC treated cohort genetic data was collected for a genome wide association analysis to scan for common genetic determinants of COIH. From our clinical experience, susceptibility to COIH varies individually. We did not observe any genome-wide significant associations, neither with sodium level in a linear trait, nor with hyponatremia as a dichotomous trait. This finding cannot rule out genetic susceptibility for COIH completely, as rare variants and combinations of genetic variants of smaller effect size may contribute to overall risk. We also assessed the clinical and genetic factors associated with CBZ metabolism. We could not replicate the finding of polymorphisms in CYP3A4 and EPHX1 (gene encoding microsomal epoxide hydrolase) that have been associated with inter-individual variability of CBZ metabolism. Also, no genome-wide significant associations with CBZ metabolic ratio were found. Hyponatremia increases the risk of hospitalisation and causes a variety of seemly mild symptoms. Treatment of COIH, by fluid restriction, dose reduction or substitution of the ASM can relieve symptoms and improve quality of life

Carbamazepine and oxcarbazepine induced hyponatremia

Epilepsy affects about 1 % of people and is mainly treated with anti-seizure medication (ASM). The use of carbamazepine (CBZ) and oxcarbazepine (OXC) as first-line ASM in treating focal epilepsy is limited by hyponatremia. This thesis describes the association between CBZ or OXC and hyponatremia and the clinical impact that carbamazepine- and oxcarbazepine-induced hyponatremia (COIH) has on people with epilepsy. We assessed the occurrence of COIH in a large cohort of people with epilepsy and looked for possible determinants. Over 2,600 people were included from our tertiary epilepsy centre in the Netherlands, and we collected data on sodium level measurements in people who (had) used CBZ and OXC. Our main finding was that hyponatremia (Na+ ≤134 mmol/L) occurred in about a quarter of those taking CBZ and almost half of those taking OXC, in line with other studies. Severe hyponatremia (Na+ ≤128 mmol/L) occurred in 7% in the CBZ group and 22% in the OXC group. Age over 40 years, high serum levels of CBZ and OXC and concomitant use of other ASMs were the main risk factors for hyponatremia in both treatment groups. Females on OXC were at a higher risk of hyponatremia than males. Symptoms present at hyponatremia, which could not be explained by another clear cause such as overt ASM intoxication or comorbidity were scored and found in almost half of people who had COIH. They lead to hospital admissions in 3%, primarily because of falls. Next we assessed the AEs experienced by people taking CBZ or OXC and whether they could be attributed to COIH. We performed an observational retrospective study collecting data between 2017 and 2019 on serum sodium levels and AEs in 410 people with COIH and 300 with normal sodium levels from our previously described cohort. Our main finding was the occurrence of AEs in 65% of people with hyponatremia compared to 21% with normal sodium levels (OR 7,5, p=<0,001) and in 83% of people with severe hyponatremia compared to 55% in those with mild hyponatremia (p=<0,001). Significant predictors of AEs were the drug (OXC vs CBZ), and the number of concomitant ASMs. Dizziness, tiredness, instability and diplopia were reported more often in the hyponatremia group than in those with normal levels. Finally we searched for genetic factors contributing to COIH. In 1,141individuals of a CBZ/OXC treated cohort genetic data was collected for a genome wide association analysis to scan for common genetic determinants of COIH. From our clinical experience, susceptibility to COIH varies individually. We did not observe any genome-wide significant associations, neither with sodium level in a linear trait, nor with hyponatremia as a dichotomous trait. This finding cannot rule out genetic susceptibility for COIH completely, as rare variants and combinations of genetic variants of smaller effect size may contribute to overall risk. We also assessed the clinical and genetic factors associated with CBZ metabolism. We could not replicate the finding of polymorphisms in CYP3A4 and EPHX1 (gene encoding microsomal epoxide hydrolase) that have been associated with inter-individual variability of CBZ metabolism. Also, no genome-wide significant associations with CBZ metabolic ratio were found. Hyponatremia increases the risk of hospitalisation and causes a variety of seemly mild symptoms. Treatment of COIH, by fluid restriction, dose reduction or substitution of the ASM can relieve symptoms and improve quality of life

Complex SCN8A DNA-abnormalities in an individual with therapy resistant absence epilepsy

Background: De novo SCN8A missense mutations have been identified as a rare dominant cause of epileptic encephalopathy. We described a person with epileptic encephalopathy associated with a mosaic deletion of the SCN8A gene. Methods: Array comparative genome hybridization was used to identify chromosomal abnormalities. Next Generation Sequencing was used to screen for variants in known and candidate epilepsy genes. A single nucleotide polymorphism array was used to test whether the SCN8A variants were in cis or in trans. Results: We identified a de nova mosaic deletion of exons 2-14 of SCN8A, and a rare maternally inherited missense variant on the other allele in a woman presenting with absence seizures, challenging behavior, intellectual disability and QRS-fragmentation on the ECG. We also found a variant in SCN5A. Conclusions: The combination of a rare missense variant with a de nova mosaic deletion of a large part of the SCN8A gene suggests that other possible mechanisms for SCN8A mutations may cause epilepsy; loss of function, genetic modifiers and cellular interference may play a role. This case expands the phenotype associated with SCN8A mutations, with absence epilepsy and regression in language and memory skills. (C) 2015 Elsevier B.V. All rights reserved