Pharmacists help reduce errors in anti-epileptic drug prescriptions

Pharmacists can help reduce errors in anti-epileptic drug prescriptions.

Clinical pharmacists can reduce anti-epileptic drug (AED) prescription errors that commonly result from incomplete or poor documentation, according to a literature review published in Seizure, The European Journal of Epilepsy. 

Researchers from the Alder Hey Children’s NHS Foundation Trust in the United Kingdom conducted a 12-month retrospective review of all pediatric outpatient prescriptions of anti-epileptic drugs (AEDs) at a large children’s hospital. In the study, the authors acknowledged that pediatric AEDs are particularly difficult to prescribe, given the wide variety of available choices and potential interactions among AEDs and other medications. 

The investigators monitored all new prescriptions for AEDs issued from the hospital’s general pediatric and pediatric neurology departments in 2012. Data was collected regarding patient demographics, diagnosis/indication for the AED, clarity of dosage instructions, prescriber details, and whether a pharmacist intervention was required prior to dispensing the medication. 

Over the course of the year, a total of 262 new AED prescriptions were written, with 19 patients receiving more than 1 AED prescription. Of those prescriptions, an astounding 72.1% were deemed incomplete with at least 1 piece of missing information, the study authors noted. 

Furthermore, 164 (62.6%) of the prescriptions did not document any diagnosis or reason for prescribing the AED. Of the remaining 98 prescriptions, 50 documented only the word “epilepsy,” while 48 described a non-epileptic diagnosis, such as “migraine,” “behavioral problems,” and “chronic pain.” 

AED prescribers recorded their designation and immediate contact details in just 41.6% of all AED prescriptions. Of those detailed prescriptions, 65.1% were written by a senior doctor, 17.4% were prescribed by a specialist trainee or junior doctor, and another 17.4% were illegible or not recorded. 

Among all epilepsy diagnoses, the most commonly prescribed AED was sodium valproate, followed by a tie between carbamezapine and levetiracetam. For prescriptions with a designated non-epileptic diagnosis, the most commonly prescribed medication was gabapentin. 

Pharmacists contacted physicians concerning 44 prescriptions (16.8%), 15 (34%) of which were due to errors in dosage or frequency of administration. Such dosing errors were identified by pharmacists for carbamazepine, gabapentin, lamotrigine, and topiramate, among other AEDs. According to the researchers, all AED prescriptions with dosing errors were amended prior to being dispensed. 

“Although there were high numbers of incomplete or inadequate prescriptions in the current study, no patients had their medication incorrectly dispensed, (which) reflects the pharmacists’ review of each prescription prior to the drug being dispensed,” the study authors concluded. “Clearly, it is the clinician’s responsibility to prescribe the most appropriate AED, but it might be reasonable to have the choice of drug confirmed by a clinical pharmacist.”

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A gene for childhood epilepsy is identified

A study using Zebrafish was used to identify a new gene associated with childhood epilepsy.

A European consortium of epilepsy researchers has reported the discovery of a new gene involved in severe childhood epilepsy. Using a novel combination of technologies, including trio exome sequencing of patient/parental DNA and genetic studies in the tiny larvae of zebrafish, the EuroEPINOMICS RES consortium found that mutations in the gene CHD2 are responsible for a subset of epilepsy patients with symptoms similar to Dravet syndrome -- a severe form of childhood epilepsy that is in many patients resistant to currently available anti-epileptic drugs.

The discovery of CHD2's role in epilepsy offers new diagnostic tools for families and clinicians of children with Dravet syndrome and related genetic epilepsies. In addition, the creation of a zebrafish model for CHD2 encephalopathy may facilitate the discovery of new drugs that can treat patients with this form of epilepsy.

Dravet syndrome is a severe genetic epilepsy with onset during infancy, with initial seizures often triggered by fever. For most Dravet patients these seizures cannot be treated adequately with currently available anti-epileptic drugs, and therefore the syndrome is classified as pharmacoresistant. Dravet patients usually develop moderate to severe cognitive delays and some features of autism, and are at increased risk of SUDEP (sudden unexplained death in epilepsy). Approximately 80% of Dravet patients have mutations in the gene SCN1A which encodes the Nav1.1 sodium channel, however for the remaining 20% of patients the underlying genetic cause has yet to be determined.

To identify novel genes involved in Dravet Syndrome and other genetic epilepsies, epilepsy clinicians and human geneticists across Europe recently initiated the EuroEPINOMICS RES (Rare Epilepsy Syndromes) consortium. In 2011, the EuroEPINOMICS RES consortium was awarded €2,37 million in funding from the national funding agencies participating in the European Science Foundation program to systematically search for novel genes for seizure disorders.

As part of these ongoing research activities, the DNA of Dravet patients without SCN1A mutations was analyzed by trio exome sequencing, which searches across the active parts of the genome for de novo mutations that have arisen in these patients (de novo mutations are DNA copying errors that occur in the parents' gametes or in the fertilized egg or embryo, resulting in the afflicted family member being the first person in their family to have this genetic condition). In a group of 9 such patients, this analysis of their DNA (and the DNA of their parents) resulted in the identification of 2 patients with de novo mutations in CHD2, which stands for chromodomain helicase DNA binding protein 2. A third patient with a CHD2 mutation was subsequently identified as well.

To confirm that mutations in CHD2 cause the epilepsy observed in these patients, the same gene was then functionally analyzed in the tiny larvae of zebrafish, which have emerged in the last decade as a powerful animal model for the study of epilepsy. In the case of CHD2, scientists collaborating with the EuroEPINOMICS RES consortium used antisense technology to rapidly generate zebrafish larvae with a partial loss of function of this gene, and were then able to detect epileptic seizures in these animals using electrographic analysis (this method is very similar to electroencephalography, or EEG, which is used to analyze seizures in humans).

The genetic analysis was led by Peter De Jonghe, head of the Neurogenetics Group of the VIB Department of Molecular Genetics at the University of Antwerp (Antwerp, Belgium) and the epilepsy genetics group in Kiel, headed by Ingo Helbig (Dept. of Neuropediatrics, University of Kiel, Germany). Peter De Jonghe: "This research reinforces our belief that trio sequencing enables us to unravel the genetic background of syndromes which occur spontaneously. Previously, investigations into the genetic causes of syndromes such as Dravet Syndrome were not feasible. These types of investigations were only possible by screening large families and seeing how a disorder was passed along. But in disorders such as Dravet Syndrome, this did not work since the children were so seriously ill that they themselves never went on to have their own children. So this new technology also opens up new perspectives in the search for the genetic background of many disorders."

Ingo Helbig adds that "the epileptic encephalopathies pose a major clinical problem as most children have treatment-resistant epilepsy, intellectual disability and many other medical issues. We hope that identifying the underlying genetic cause will help us find better treatment options for the affected patients. In the past, we were not able to identify the reason why children have severe epilepsy. The discovery of CHD2 as the culprit gene in a subset of children with epileptic encephalopathy is a major step for us."

The zebrafish research was led by Camila Esguerra of the Laboratory for Molecular Biodiscovery of University of Leuven (Leuven, Belgium). She commented: "Our previous research to validate zebrafish as a model for epilepsy put us in a good position to be able to help the EuroEPINOMICS consortium investigate the function of CHD2. The zebrafish larva is an ideal model to study genes involved in epilepsy, and the methods necessary for such studies are now well-established in our laboratory. Looking forward, our zebrafish models of pharmacoresisant epilepsy are well-suited for large-scale pharmacological screens to find new anti-epileptic drugs."

The Dravet Syndrome Foundation EU (DSF-EU, Madrid, Spain) is a patient organization dedicated to finding a cure for Dravet Syndrome, and also works to promote awareness of the disease and to help families of Dravet patients. Julian Isla, Executive Director of DSF-EU, stated: "One of the most important things for patients with genetic disorders and their families is to be able to give a name to the gene causing their disease. When it comes to Dravet syndrome, the genes responsible for up to 20% of the cases are still unknown. The discovery that mutations in CHD2 cause a Dravet-like syndrome means some of these patients will now have access to better genetic diagnosis and therefore provide much-needed answers to these families. Importantly, the development of a new animal model for Dravet syndrome based on reduced CHD2 expression might help to find effective treatments that could improve the lives of thousands of people suffering from Dravet syndrome and perhaps other genetic epilepsies."

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The effect of anti-epileptic drugs on children's growth

A recent study looked into how the use of anti-epilepsy drugs effects children's growth and health, and results showed that the use of certain drugs to impair the growth of children with epilepsy.

This study investigated whether long–term treatment with antiepileptic drugs (AEDs) had negative effects on statural growth and serum calcium levels in children with epilepsy in Taiwan. These results raise serious concerns about the growth of pediatric epilepsy patients who use AEDs, and potentially the need to closely monitor growth in children with epilepsy and adolescents under AED treatment, especially VPA.

Methods

• Children with epilepsy treated with one prescription of AEDs (monotherapy) for at least 1year were selected.
• The AEDs included valproic acid (VPA; Deparkin) in 27 children (11 boys and 16 girls) aged 4-18years, oxcarbazepine (Trileptal) in 30 children (15 boys and 15 girls) aged 5-18years, topiramate (Topamax) in 19 children (10 boys and 9 girls) aged 6-18years, and lamotrigine (Lamicta) in eight children (5 boys and 3 girls) aged 5-13years.
• Patients with a history of febrile convulsions were selected as the controls.

Results

• One year of VPA treatment significantly impaired the statural growth of pediatric patients with epilepsy (p<0.005) compared with the control group.
• The underlying mechanism may have been due to the direct effect of VPA on the proliferation of growth plate chondrocytes rather than alterations of serum calcium.

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Inflammation can be caused by anti-epilepsy drugs

A report claims that anti-epilepsy drugs can cause inflammation and thus may have roots in the immune system.

Physicians at the Ruhr-Universität Bochum (RUB) have been investigating if established anti-epilepsy drugs have anti-inflammatory or pro-inflammatory properties -- an effect for which these pharmaceutical agents are not usually tested. One of the substances tested caused stronger inflammations, while another one inhibited them. As inflammatory reactions in the brain may be the underlying cause for epileptic disorders, it is vital to take the trigger for the disorder under consideration when selecting drugs for treatment, as the researchers concluded. They published their report in the journal Epilepsia.

Glial cells play a crucial role in the nervous system

Hannes Dambach from the Department for Neuroanatomy and Molecular Brain Research, together with a team of colleagues, studied how anti-epilepsy drugs affect the survival of glial cells in cultures. Glial cells are the largest cell group in the brain; they are crucial for supplying neurons with nutrients and affect immune and inflammatory responses. The question of how glial cells are affected by anti-epilepsy drugs had previously not been studied in depth. The RUB work group Clinical Neuroanatomy, headed by Prof Dr Pedro Faustmann, analysed four substances: valproic acid, gabapentin, phenytoin and carbamazepine.

Four anti-epilepsy drugs affect glial cells in different ways

Glial cells treated by the researchers with valproic adic and gabapentin had better survival chances than those treated with phenytoin and carbamazepine. However, carbamazepine had a positive effect, too: it reduced inflammatory responses. Valproic acid, on the other hand, turned out to be pro-inflammatory. In how far the anti-epilepsy drugs affected inflammations was also determined by the applied dose. Consequently, different drugs affected glial cells -- and hence indirectly the neurons -- in different ways.

Inflammatory responses should be taken under consideration in clinical studies

"Clinical studies should focus not only on the question in how far anti-epilepsy drugs affect the severity and frequency of epileptic seizures," says Pedro Faustmann. "It is also necessary to test them with regard to the role they play in inflammatory responses in the central nervous system." Thus, doctors could take the underlying inflammatory condition under consideration when selecting the right anti-epilepsy drug.

Epilepsy may have different causes

In Germany, between 0.5 and 1 percent of the population suffer from epilepsy that requires drug treatment. The disease may have many causes: genetic predisposition, disorders of the central nervous system after meningitis, traumatic brain injury and stroke. Inflammatory responses may also be caused by damage to the brain.

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Moms with epilepsy should breastfeed their infants

A study shows that breastfeeding mothers with epilepsy should continue to breastfeed their children regardless of taking antiepileptic drugs while breastfeeding. JR

The study aims to determine whether signs of impaired development appear already during the first months of life in children exposed prenatally to antiepileptic drugs, and to explore potential adverse effects of antiepileptic drug exposure through breastfeeding. Prenatal exposure to antiepileptic drugs was associated with impaired fine motor skills already at age 6 months, especially when the child was exposed to multiple drugs. There were no harmful effects of breastfeeding. Women with epilepsy should be encouraged to breastfeed their children irrespective of antiepileptic drug treatment.

Methods

• Mothers at 13 to 17 weeks of pregnancy were recruited in the population-based, prospective Norwegian Mother and Child Cohort Study from 1999 to 2009.
• The mothers reported on their child’s motor and social skills, language, and behavior using items from standardized screening tools at 6 months (n=78744), 18 months (n=61351), and 36 months (n=44147) of age.
• The mothers also provided detailed information on breastfeeding during the first year.
• The risk of adverse development in children according to maternal or paternal epilepsy was estimated as the odds ratio with corresponding 95% confidence interval, adjusted for maternal age, parity, education, smoking, breastfeeding, depression/anxiety, folate supplementation, and congenital malformation in the child.

Results

• At age 6 months, infants of mothers using antiepileptic drugs (n=223) had a higher risk of impaired fine motor skills compared with the reference group (11.5% vs 4.8%, respectively; odds ratio=2.1; 95% CI, 1.3-3.2).
• Use of multiple antiepileptic drugs compared with the reference group was associated with adverse outcome for both fine motor skills (25.0% vs 4.8%, respectively; odds ratio=4.3; 95% CI, 2.0-9.1) and social skills (22.5% vs 10.2%, respectively; odds ratio=2.6; 95% CI, 1.2-5.5).
• Continuous breastfeeding in children of women using antiepileptic drugs was associated with less impaired development at ages 6 and 18 months compared with those with no breastfeeding or breastfeeding for less than 6 months.
• At 36 months, prenatal antiepileptic drug exposure was associated with adverse development regardless of breastfeeding status during the first year.
• Children of women with epilepsy who did not use antiepileptic drugs and children of fathers with epilepsy had normal development at 6 months.

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FDA approved marijuana-based CLINICAL TRIAL to treat Epilepsy

PLEASE NOTE: The FDA has recently approved a clinical trial  or an experiment with a marijuana-base to treat epileptic disorders. The agent has not been approved for clinical use. If interested call the study sponsors below.  JR

The US Federal Drug Association approved clinical studies that aim to determine whether purified cannabidiol (CBD) is a viable anti-seizure treatment. Physician investigators will be provided with Epidiolex, a new 98% CBD product made by GW Pharmaceuticals, and conduct Investigational New Drug studies involving epileptic children.

According to O’Shaughnessy, the clinical studies will be sponsored by Orrin Devinsky, MD, at the NYU School of Medicine, and Roberta Cilio, MD, PhD, at University of California, San Francisco. Both are expected to monitor the progress of 25 patients, but they may enroll more with approval from the FDA. Additionally, Cilio will conduct two individual studies as well.

GW Pharmaceuticals, the British company responsible for the cannabis-based spray Sativex, will provide researchers with their latest “pure CBD” product – Epidiolex. The drug will come in the form of a viscous liquid to be dispensed in syringe droppers. Additionally, there will be two strengths available: 25 milligrams per milliliter and 100 mg/ml.

According to GW, Epidiolex contains no tetrahydrocannabinol (THC), the psychotropic component in cannabis. It is said to contain more than 98% cannabidiol (CBD) and trace amounts of other cannabinoids. GW chairman Geoffrey Guy, MD, told O’Shaughnessy, “Our definition of pure is no THC.”

Guy believes the studies will help provide “better understanding and experience in what cannabidiol does in these different children groups, what benefit we can see, and how the results can best be measured.”

Considering anecdotal evidence that cannabis can help treat epileptic seizures, and nearly 5 years of pre-clinical trial data from GW Pharmaceuticals, Guy expects more studies to come in the future.

“In the coming months, if the FDA is comfortable about how things are going, there will be a number of senior epileptologists in major university centers throughout the U.S., each treating a couple of dozen patients with various epilepsies,” he explained.

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Epilepsy Drug Sodium Valproate Linked to Increased Chance of Autism and ADHD during Pregnancy

Children to mothers who took epilepsy drug sodium valoprate while pregnant have an increased risk of developing autism. These children should be watched closely.

Children born to mothers who took the antiepileptic drug sodium valproate during pregnancy are at significantly increased risk of autism and other neruodevelopmental disorders.

The finding came from new research published in the Journal of Neurology, Neurosurgery and Psychiatry

The research involved kids born to 528 pregnant women in England between 2000 and 2004. Fifty percent (243) of the moms had epilepsy, only 34 of those women did not take antiepileptic drugs while pregnant.

Carbamazepine was taken by 59 of the women, valproate was taken by another 59 women, lamotrigine was taken by 36, forty-one of the females took a combination, and 15 took other medications.

The researchers evaluated the physical and intellectual development of the kids at 12 months, three years, and 6 years of age.

The mothers also provided the scientists with information on whether they ever had to seek professional advice concerning their child's development, behavior, health, or educational progress.

There were 415 kids who had complete data on all 3 evaluations. A neurodevelopmental disorder was diagnosed in 19 kids by the time they were 6 years old, three of those children were affected by a physical abnormality.

Twelve of these kids had a form of autism, one child also had ADHD (attention deficit hyperactivity disorder). Three had ADHD alone and another four had dyspraxia - a condition that causes poor physical coordination and uncontrolled clumsiness.

The experts discovered that neurodevelopmental issues were notably more prevalent among those kids whose mothers had epilepsy - 7.46% vs. 1.87% of those whose mothers did not struggle with the condition.

The children whose moms took valproate by itself or with another drug during pregnancy had a considerably higher chance of being diagnosed with a neurodevelopmental condition, compared to those whose mothers took other medications for their disorder.

After examining all of the figures and adjusting for factors likely to impact the results, the investigators found that kids exposed to valproate in the womb were 6 times more likely to have a neurodevelopmental disorder.

Kids who were exposed to valporate and other drugs were 10 times more likely to have a neurodevelopment disorder than those whose moms did not have epilepsy.

Six out of 50 children (12%) whose mothers had taken valproate alone while pregnant had a neurodevelopmental problem, as did 3 out of 20 (15%) of those whose mothers had taken valproate with other treatments.

The women who had epilepsy and did not take drugs to treat the condition during pregnancy did not have any children diagnosed with a neurodevelopment disorder. However, the experts noted, there was only a small number of females in this group.

Boys had a 3 times higher chance of being diagnosed with a nuerodevelopmental disorder. However, no notable links were identified for the mother's age or IQ, epileptic seizure type, or length of pregnancy.

Although further studies are necessary before conclusions can be drawn, the findings of this research support prior reports that have demonstrated that there are potentially negative effects of valproate on the developing fetus.

For example, one study indicated that kids born to moms who took valproate while pregnant tended to score notably lower in IQ tests by an average of 6 to 9 points at age 3, than kids born to moms who took other anti-epilepsy drugs.

The experts concluded:

"If sodium valproate is the treatment of choice, women should be provided with as much information as possible to enable them to make an informed decision.

But on no account should pregnant women just stop taking the drug for fear of harming their developing child," the scientists concluded."

The researchers added that kids born to mothers who took the medication while pregnant need to be observed closely.


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