Is Refractory Epilepsy an Epilepsy Misdiagnosis?

Refractory epilepsy, is the form of epilepsy which involves the patient being unable (or no longer being able) to respond to the prescribed epilepsy medication. For most conditions, if a patient is not responding to their medication, it may flag as a misdiagnosis or that the specific medication is not effective. However, in refractory epilepsy, the term is given as a diagnosis whilst defining the concept that the patient is correctly diagnosed with epilepsy but is not responding to even the best medical treatment. This, to me, sounds very peculiar as surely if it still is epilepsy, then the usual AEDs (anti-epileptic drugs) should remain effective?

This raises the question of why it is the case that some have a confirmed diagnosis of epilepsy yet seem to be unresponsive to the treatments prescribed? Perhaps it is a result of a resistant gene? Or is it due to lifestyle changes that may have resulted in an epigenetic change or limits how well the medication works? Or could it be the case that the seizures aren’t epileptic in the first place and are instead pseudoseizures or something completely different?

PSYCHOGENIC

Around 25% of patients with refractory epilepsy are misdiagnosed, which suggests that the condition they are suffering from may not even be epilepsy at all. This means that the patient has a different condition, which must be identified. However, if the diagnosis is later corrected and seizures are controlled with different treatment, then it is not refractory. Incorrect epilepsy diagnoses are fairly common, as symptoms of epilepsy vary and may overlap with symptoms of other disorders. Examples of these conditions are mental health conditions (e.g. schizophrenia), eclampsia (seizures in pregnant people: high blood pressure, headaches, blurry vision and convulsions), sleep disorders (e.g. narcolepsy: brain unable to regulate sleeping and waking patterns- sleep attacks, sleep paralysis etc.), psychogenic seizures (e.g. dissociative seizures: episodes of involuntary movements due to psychological distress) and many others. I will first be discussing the potential of psychogenic seizures being misdiagnosed as epilepsy.

A common form of psychogenic seizure that is often confused with epileptic seizures, is dissociative seizure. Dissociative seizures are considered as a ‘complex and debilitating neuropsychological condition’ by ‘Ormond Neuroscience’. They are believed to be an unconscious and involuntary response to psychological stress. Video electroencephalography (VEEG) is often the best way to distinguish between the psychogenic seizure and epileptic seizure diagnosis. This method records the outward appearance of the event on video as well as recording the electrical activity of the brain that occurs before, during and after the event, however psychogenic seizures do not have any associated abnormal electrical activity of the brain, which is not the case for epileptic seizures. The diagnosis of dissociate seizures is often difficult as many patients tend to resist the idea that their seizures are caused by psychological problems rather than neurological problems. In terms of treatment, the diagnosis should be followed by psychotherapy, along side psychotropic medications as there is evidence for psychiatric comorbidities.

GENETIC

Recently, many studies have shown that genetic variation may be involved in the drug resistance of epilepsy. In particular, genetic variations found in drug-resistance related genes may be a potential cause. These involve: voltage-dependent sodium and potassium channel genes or the metaboliser of endogenous and xenobiotic substances genes.

Studies have suggested that the physiopathological basis of refractory epilepsy are pharmacokinetic and pharmacodynamic mechanisms. Pharmacokinetics involves the impairment for the AED to achieve optimal concentration levels at the site of action- where it is mainly influenced by the lip solubility, absorption, metabolism, and elimination of the drug. Pharmacodynamics involves factors like synapses, ion channels and receptors that alter the action of the AED in the site of action. This is due to: alteration involving transporters, modifications to pharmacological targets due to genetic alterations that may be linked to the disease. Some of the most important genes associated with the physiopathology of epilepsy were associated with the: neuronal acetylcholine receptor, neuronal potassium channel, voltage-dependent sodium channels, calcium channels and GABA receptors.

GABA receptors are a major target for AEDs, therefore if there are issues with the GABA receptors, then this may lead to drug failure. The role of GABA is to reduce neuronal excitability and regulate muscle tone. I tis able to send it inhibitory message by binding at GABA-A receptors on the outside of the receiving neuron, this neuron then opens a channel to allow chloride ions to pass into the neuron. The chloride ions result in the neuron being less responsive to other neurotransmitters that would usually excite it. Some AEDs (e.g. benzodiazepines) bind to their own receptors that are on the GABA-A receptor and when it is bound, it will further boost the actions of GABA, allowing more chloride ions to enter the neuron- making it more resistant to excitation (where excitation can lead to seizures, so this reduces the risk of developing a seizure).

However, long term usage of Benzodiazepine can lead to the uncoupling of the GABA-A receptor, which leads to a decrease in the ability of Benzodiazepines helping GABA’s action on receptors. This could be due to changes in the GABA-A receptor gene expression which results in impacting the binding of benzodiazepine to the receptors.

CONSEQUENCES OF MISDIAGNOSIS Patients who are wrongly prescribed AEDs will inevitably experience damaging side-effects that may further negatively impact their lifestyle. Examples of side-effects of AEDs include: moderate impairment of cognitive functioning, daytime sleepiness, gingivitis (inflammation of gums) and potentially liver toxicity if the dosage is too high (which may occur if the doctor feels upping dosage may be more effective). The consequences of these side-effects involve: the patients being unnecessarily hospitalised, absences at work, banned from driving etc.. These are impacts that could limit their ability to generate income, further impacting their financial stability and socioeconomic levels. For a minority, there may be risks of iatrogenic complications (illness caused by a medication or physician). An example would be AED toxicity or potentially vocal cord injury during intubation when in ‘status pseudo-epilepticus (15% of patients hospitalised for psychogenic nonepileptic attacks were intubated and these patients tend to have longer hospital stay lengths due to more complications, but intubation is required to provide a secure airway and minimise risk of aspiration- when something enters your airways by accident).

As mentioned previously, for those who were initially diagnosed with epileptic seizures and then diagnosed with psychogenic seizures, comprehending the information that it is a psychological problem can be difficult. This is because their lives would have been structured for a period around the belief that they are suffering from epilepsy, so having to suddenly change your perception on this may be initially difficult. This is why the communication of the diagnosis being delivered skilfully and carefully is so important for the patient’s likelihood to accept diagnosis and can result in seizure frequency decreasing by more than a half. One study found that 20% of patients diagnosed with dissociative seizures attempt suicide within 18 months of being given the diagnosis, which emphasises the requirement for careful communication and relevant support post-diagnosis.

BUT WHAT IF IT IS A CORRECT DIAGNOSIS?

In many cases, of course, refractory epilepsy is still epilepsy but simply the fact that the medications have stopped working or that the electrical activity in the brain during a seizure may be getting so high that medications are no longer able to control it. These cases leave the patient at great risk as there is evidence from studies that shows, within epilepsy, mortality is greatest for those with refractory epilepsy as it is simply left untreated and left to progress into potentially SUDEP (sudden unexpected death in epilepsy). Maximising seizure control is said to be the only proven method of decreasing risk of SUDEP, therefore this is suggestive that refractory epilepsy may leave patients at a greater risk of SUDEP than those with effective AED responses.

CONCLUSIONS

Research into the causes of refractory epilepsy should be prioritised more, to gain a better understanding of the potential genetic, environmental or decisional influences involved. Whether it be through advances in genomic technologies, improving awareness on early detection for signs of epilepsy, developing potential personalised AEDs or improving the method in which clinicians analyse the patient’s signs and symptoms before concluding the diagnosis, all of these potential methods of improvement should be considered. With this being done, better care could be guaranteed for the growing number of patients with refractory epilepsy, soon allowing them to live a life of better quality and certainty than the unknown they currently face on a daily.