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An update on the presentation, diagnosis, and treatment of epilepsy and the latest Irish research in the area
Epilepsy is the collective term for a large group of anatomical and functional disorders of the brain, characterised by repeated seizures; brief episodes of involuntary movement that may involve a part of or the entire body.
In Ireland, up to 40,000 people are affected by epilepsy. Globally, over 50 million people are affected and an estimated 2.4 million people are diagnosed with epilepsy each year. Epilepsy has significant social and economic implications in terms of healthcare needs, premature death and workplace productivity. The risk of premature death in people with epilepsy is up to three times higher than the general population, with highest rates found in low- and middle-income countries and rural versus urban areas. (WHO, 2018; Epilepsy Ireland, 2018).
Idiopathic epilepsy is the most common type, and in over half of cases there is no known cause. Epilepsy with a known cause is called secondary or symptomatic epilepsy. The causes of secondary epilepsy include: Brain damage from prenatal or perinatal injuries; congenital abnormalities or genetic conditions with associated brain malformations; severe head injury; stroke (CVA) that restricts the amount of oxygen to the brain; infections of the brain, such as meningitis, encephalitis, or neurocysticercosis; and genetic syndromes and brain tumours.
To make a diagnosis of epilepsy, it is necessary to establish a tendency to experience recurrent, spontaneous epileptic seizures. Many people have a single, isolated epileptic seizure at some point in their lives, but if a person has more than one, then a diagnosis of epilepsy may well be considered. Seizures can vary, from the briefest lapse of attention or muscle jerks, to severe and prolonged convulsions accompanied by loss of consciousness and control of bladder and bowel function. They can also vary in frequency, from less than one per year, to several per day. Characteristics of seizures vary, depending on where in the brain the disturbance occurs, and how far it spreads. Temporary symptoms occur, such as loss of awareness or consciousness, disturbances of movement and sensation (including vision, hearing and taste), mood, or other cognitive functions. Certain triggers which make seizures more likely include missed medication, increased alcohol intake, sleep deprivation, stress, illness and fevers (WHO, 2018).
A clinical diagnosis of epilepsy is made through a detailed case history, by considering eye witness descriptions of seizures and also various test results. Tests include the routine awake EEG, sleep and sleep-deprived EEG, and either CT brain scan or MRI. Often, tests are normal but a diagnosis can still be made. Routine blood tests may be ordered. In addition, as knowledge and technology improves, diagnosis of epilepsy is changing. Around 30 per cent of children with early-onset epilepsy can now receive a precision diagnosis through genomic sequencing, with Irish research showing significant progress in this area (see panel).
The main treatment for epilepsy is antiepileptic drugs (AEDs), although surgery may be required for severe cases. The potential for drug-drug interactions should always be considered when prescribing concomitant medication to a patient on AEDs and the National Medicines Information Centre (NMIC) provides up-to-date information on AED-related enquiries. Drug-drug interactions occurring in patients with epilepsy can have substantial effects on clinical outcome and may often be predicted by the pharmacokinetic (PK) and pharmacodynamic (PD) profiles of the AEDs. Many patients with epilepsy have comorbid conditions that require non-AED concomitant medications. Drug interactions between AEDs and contraceptive hormones are clinically important and need to be considered due to risks including contraceptive failure, potential teratogenicity of AEDs and reduced seizure control. There are widespread concerns about the teratogenic risks posed by AEDs, and care must be taken with use in pregnancy. In view of the increased risk of neural tube defects and other major congenital malformations associated with exposure to AEDs (particularly sodium valproate and carbamazepine), current guidelines recommend that a daily dose of 5mg folic acid is prescribed prior to conception and until at least the end of the first trimester for all women taking AEDs (NMIC, 2014). However, it must be stressed that current understanding is that while it may decrease the risk of neural tube defects that may occur in all pregnancies, available evidence does not suggest folic acid prevents the birth defects or malformations due to valproate exposure.
A full list of current AEDs and potential side-effects are available at www.epilepsy.ie/content/types-anti-epileptic-drugs-aeds. See panel for expert update on epilepsy pharmacological treatment.
Valproate-containing medicines (also known as sodium valproate or valproic acid) are approved in Ireland under the brand name Epilim, to treat epilepsy and bipolar disorder. Valproate can cause birth defects and problems with the development and learning of the child if their mother takes this medicine during pregnancy. Children exposed in utero to valproate are at a high risk of serious developmental disorders (in up to 30-40% of cases) and congenital malformations (in approximately 10% of cases).
In 2014, an EU-wide review led to strengthening of restrictions for use of valproate and further characterisation of the risk of birth defects and developmental disorders in the product information (Summary of Product Characteristics (SmPC) and Package Leaflet (PL)). The impact of the risk minimisation measures was the subject of a further review initiated in 2017 and the recommendations arising from this review were published and endorsed in February and March 2018.
There are now important new contraindications, strengthened warnings and measures to prevent valproate exposure during pregnancy. Valproate must not be used in girls and women who may be able to have children unless the terms of the pregnancy prevention programme are followed. This programme includes measures to ensure patients taking valproate (Epilim) are fully aware of the risks and the need to avoid becoming pregnant while taking it. Details of the pregnancy prevention programme are listed in section 4.4 of the SmPC which is part of the product information. It is important that women and girls who have been prescribed valproate should not stop taking their medicine without consulting their doctor
Nearly 80 per cent of people with epilepsy live in low- and middle-income countries. It accounts for 0.6 per cent of the global burden of disease. Diagnosis and treatment of most people globally with epilepsy occurs in primary care without the use of sophisticated equipment. In low- and middle-income countries, however, 75 per cent of people with epilepsy may not receive the treatment they need. A recent study (Megiddo et al, 2016) found the average availability of generic antiepileptic medicines in the public sector of low- and middle-income countries to be less than 50 per cent. This may act as a barrier to accessing treatment (WHO, 2018).
Although social effects vary from country-to-country, people living with epilepsy can be targets of prejudice. Discrimination and social stigma surrounding epilepsy worldwide are often more difficult to overcome than the seizures themselves. The stigma of the disorder can discourage people from seeking treatment for symptoms, so as to avoid becoming identified with the disorder.
Epilepsy Ireland carries out tremendous work to raise awareness, and offers a wide range of services and supports for people with epilepsy in Ireland and their families. Their aim is to ‘achieve a society where no person’s life is limited by epilepsy’. With headquarters in Dublin and regional offices in Cork, Dundalk, Galway, Kerry, Kilkenny, Letterkenny, Limerick, Sligo and Tullamore, the website also offers invaluable information and resources for epilepsy patients and is available at www.epilepsy.ie.
References on request
Epilepsy treatment considerations
Paul Mulholland and Priscilla Lynch
A key presentation at the recent Irish Neurology Association (INA) Neurology Update meeting in Belfast focused on when to start and cease anticonvulsant therapy for epilepsy patients, and was delivered by Dr Norman Delanty, Consultant Neurologist in Beaumont Hospital, Dublin.
Dr Delanty told delegates it should be remembered that there are many people with undiagnosed epilepsy, and it is important to ask whether a ‘first seizure’ experienced by a patient is really their first seizure.
“The convulsion is often the ‘straw that breaks the camel’s back’ and brings the patient to medical attention,” according to Dr Delanty.
“Following clinical assessment, if prior unrecognised, unappreciated seizures, then the decision to start medication is usually easy.”
He said the overall risk of recurrence in those with first seizure is 35 per cent within three-to-five years.
Dr Delanty then provided a list of issues to consider when initiating or choosing an anticonvulsant medication:
Was it a seizure? Was the seizure provoked or unprovoked?
Was it the first seizure?
Are there risk factors for epilepsy?
Is there a recognisable underlying epilepsy syndrome?
What are the potential consequences of further seizures?
How urgent is treatment initiation?
Factors to consider when choosing the type of anticonvulsant are:
Evidence from clinical trials and post-marketing experience.
Epilepsy syndrome and seizure type.
Seizure severity and density.
Age and sex.
Current (and future) reproductive intentions.
Medication adherence considerations.
Dr Delanty said that treatment should be individualised considering the risk/benefit ratio of each option. These considerations include:
The appropriateness of drug to seizure type.
Dosage and titration regimens.
Risk of adverse drug reactions.
Dr Delanty then went on to describe the value of ‘rescue therapy’, or pharmacological first-aid, with medications such as buccal midazolam and clobazam.
“All or most patients and families should be prescribed and counselled about this,” according to the consultant neurologist. He also pointed out the importance of advanced nurse practitioners with regard to patient education, who must realise that such medication needs to be taken early in the event of a seizure, while stating that the medication prescribed should be “individualised” for each patient.
Clinicians and patients need to recognise the potential side-effects of anticonvulsants. These might be dose-related (dizziness, nausea, fatigue); idiosyncratic or unpredictable (rash, tremor, blood dyscrasia); chronic due to cumulative drug exposure (weight gain/loss, mood change); teratogenic/carcinogenic effects (VPA/TPM); and adverse events due to drug interactions (CBZ/macrolides, inducers/bone loss).
Dr Delanty noted the challenge of oligo-epilepsy, which refers to the rare or uncommon occurrence of seizures in an individual over their lifetime. Again, he stated that treatment should be individualised and that while it may be reasonable to forgo regular medication, rescue benzodiazepines were important.
With regard to stopping antiepileptic drugs for patients on regular medication, Dr Delanty said “there are no hard and fast rules”. He said any decisions need to be based on a detailed discussion between the patient and the neurologist.
Any withdrawal off medication needs to occur “slowly” and it is also important to remember, he said, there is generally a 30-to-45 per cent chance of relapse for people who come off their medication. Consideration needs to be given to what the consequences of a relapse would be for a patient who is currently seizure-free, with the impact on driving especially important.
“If the patient is not seizure-free or has significant side-effects on their quality-of-life, then the decision is easy or easyish,” Dr Delanty said. Such patients should be put on a non-enzyme inducing agent.
However, if the patient is seizure-free and has no significant side-effects and a good quality-of-life, the decision is not so easy. These patients can either be “left as is”; have their medication withdrawn slowly; or be put on a non-enzyme inducing agent.
Dr Delanty also pointed out that if a patient stops their regular anticonvulsant therapy, but needs to begin therapy again at a later date should seizure reoccur, “10-to-20 per cent will not regain easy control in this setting and may change to drug-refractory epilepsy”.
While the risks for pregnant women taking sodium valproate are now well recognised, speaking to the Medical Independent (MI) earlier this year, Dr Delanty confirmed that there are a number of other epilepsy medications that doctors have concerns about regarding potential teratogenicity.
“I think the numbers here are small but there are other drugs such as topiramate, which is used for epilepsy and migraine, where there is some concern about teratogenicity. Some of the older drugs like phenytoin and phenobarbital are not completely safe either so valproate is probably the worst, but it is not the only drug where there are concerns about safety in pregnancy and that has to be discussed between the patient and the doctor, because even sodium valproate sometimes has to be used in pregnancy, as it is the only drug that controls some people’s seizures. So if a woman is having convulsions all the time, falling down, injuring herself, injuring her baby and if the only drug that controls the seizures is, for example, sodium valproate, then that may be the only choice, but there are concerns with other drugs. And with the newer drugs, we don’t have any good pregnancy data, which is why we need pregnancy registries worldwide. There is always going to be a trade-off between risk of the treatment and risk of active disease.”
FutureNeuro researchers integrate genomics data into electronic patient records
Researchers from the HSE Epilepsy Lighthouse Project and FutureNeuro, the SFI Research Centre for Chronic and Rare Neurological Diseases hosted by the RCSI, have developed a new genomics module in the Irish National Epilepsy Electronic Patient Record (EPR) system.
The work illustrates how an electronic health system can support the integration of genomic test results and new genetic knowledge into routine clinical care in the public health system. This new system will facilitate more personalised forms of medicine.
The research, funded by eHealth Ireland, HSE and Science Foundation Ireland, was published recently in the journal Epilepsia.
Many adults and children with epilepsy of unknown cause now undergo genomic testing.
“We now know that much of previously unexplained epilepsy is due, in part, to damaging variants in a person’s genome,” said Prof Norman Delanty, Associate Professor at the RCSI, FutureNeuro Investigator and Consultant Neurologist at Beaumont Hospital, Dublin.
“The potential to understand the reason for a particular person’s epilepsy at a molecular level, and to use this information to develop personalised therapies, will become a significant advancement in the way we practice medicine.”
Ireland has a world-leading national EPR system designed specifically for epilepsy. This system captures, in great depth, the subtle patient features relevant to specialist care and allows for quicker access to key clinical data to better support people with complex chronic diseases such as epilepsy. In 2015, the HSE and eHealth Ireland designated the national Epilepsy EPR as a ‘Lighthouse’ project for the country to help build an understanding of the quality, safety, and efficiency benefits of EPRs. The Lighthouse project combined the emerging fields of genomics and EPRs to promote personalised medicine and improved healthcare for people with epilepsy.
“The epilepsy EPR system is one of the largest, most detailed collections of active epilepsy eHealth records in the world,” said Ms Mary Fitzsimons, FutureNeuro Epilepsy eHealth Lead and Director of the Epilepsy Lighthouse Project at the RCSI. “To our knowledge, the epilepsy genomics module we have developed is the first such specific system in the world. We believe the combined power of genomics and electronic patient records has the capability of enhancing, and in some cases transforming, the practice of medicine.”
The new Epilepsy EPR module facilitates regular multidisciplinary meetings between clinicians, geneticists, bioinformaticians, and other team members, where they review data from genomic testing to determine if there is an identifiable genetic cause for a person’s epilepsy.
“Diagnostic genomic testing is a rapidly-growing area in clinical medicine, but there is much work to be done to understand the most effective way to integrate this powerful information into patient care. We hope this new eHealth technology can inform how genomics is integrated into the Irish healthcare system and act as an example for other diseases beyond epilepsy,” said Prof Gianpiero Cavalleri, FutureNeuro Deputy Director and Professor of Human Genetics at the RCSI. “Having this data available in a person’s secure electronic record enables multidisciplinary teams to quickly make better decisions about a person’s treatment options.”