Diseases and Disorders

Modern Approaches in the Diagnosis and Treatment of Epilepsy

Shivangi Chaturvedi


Abstract

Coined by Hippocrates in the 6th century, epilepsy is amongst the most widely known neurodegenerative disorders characterized by sudden, abnormal, and recurrent events of sensory disturbance, loss of consciousness, or convulsions. The diagnostic criteria developed for the identification of epilepsy in clinical practice is mainly through neurological examinations such as EEG, MRI, and CT scans. Even after the development of modern treatment approaches including symptomatic therapies, surgeries, neuronal implants; epilepsy continues to affect 50 million people worldwide. This article encompasses historical advancements and modern research developments to treat epilepsy in the current scenario.

 

Introduction

One of the earliest recorded observations about epilepsy was in  1067-1049 BC, when the Babylonians believed that epilepsy or “Sakkikumiqtu”, which translates to “falling sickness”, was caused by ghosts or demons These Babylonians, treated epilepsy as an unusual supernatural act. They had described a few clinical forms: generalized, gelastic (which means laughter), chronic convulsions, and postictal states. Around 400 BC, physicians of the Hippocratic School in Greece were aware of epileptic seizures emerging in the brain. Several hundred years later, Galen of Pergamon (130-200 AD) stated that epilepsy was viewed as a rather mysterious condition consisting of supernatural attributes in the West until at least the mid-nineteenth century. However, the first time epilepsy was ever mentioned was in the writings of ancient Mesopotamia and Indian Ayurvedic texts which date back to about 3000 years ago [1][2].

Characterized by the tendency to have recurrent unprovoked seizures, epilepsy is a disorder of the Central Nervous System (CNS), specifically the brain. The brain is a composition of billions of neurons or nerve cells that communicate with each other through chemical or electrical signals.  When there is a sudden excessive electrical discharge disrupting the normal functioning of the nerve cells, a seizure emerges. A seizure is a brief, abnormal, excessive surge of electrical activity in the brain that produces a notable change in behavior. A person is found to experience body sensations such as a pricking sensation by pins or needles, smells, sounds, fear, depression, distortions of sensory stimuli, momentary jerks or head nods, staring with loss of awareness, and convulsive movements. Seizures usually last anywhere from seconds to minutes and rarely longer than that. The immediate period after the seizure is called the postictal period. While it is difficult to predict when a person will experience a seizure, many people have experienced a déjà vu or an “aura” as an early warning feeling of a seizure.  An aura is a strange sensation or feeling which in fact, is a simple partial seizure, a form of seizure. Auras may consist of dizziness, an unusual feeling in the stomach, buzzing in the ear, or powerful emotion [2][3].

 

Types of Epilepsy

There are two types of epilepsy: idiopathic and symptomatic. Idiopathic epilepsy does not have any specific anatomical cause for the eruption of the seizure. On the other hand, symptomatic epilepsy is the type where the emergence of epilepsy has known causes. For example, it might be caused due to some past traumatic incidents, head injury, tumor, hypoglycemia, or alcohol withdrawal, etc.  If a person experiences two or more seizure outbreaks within a defined period of time,  then it is called symptomatic epilepsy [3].

 

Classification of Epilepsy

Partial seizures are the ones in which the seizure activity originates in any one part of the brain. Based on the brain region involved, partial seizures are further classified into simple partial seizures or Jacksonian seizures, complex partial seizures or temporal lobe/psychomotor seizures, and partial seizures which evolve into generalized seizures.

In generalized seizures, seizure activity involves the entire brain. They are further classified into tonic seizures, clonic seizures, tonic-clonic seizures, absence seizures, atonic seizures, myoclonic seizures, akinetic seizures, and infantile seizures [4].

 

Etiology

While there are many probable and known causes of seizures , a past head injury or trauma is the most common among others. Many times, certain brain conditions that cause damage to the brain such as brain tumors or strokes can also cause epilepsy. Infectious diseases like meningitis, AIDS, and viral encephalitis also contribute to the onset of seizures. Before birth, babies are sensitive to brain damage. While this can be caused because of several reasons, infection in the mother and poor nutrition or oxygen deficiencies are the most commonly observed causes that result in epilepsy or cerebral palsy. Epilepsy sometimes might be associated with developmental disorders such as autism and neurofibromatosis. Insufficiency of essential substrates required for membrane functioning or cellular metabolism, intracellular accumulation of toxic substances, or alteration of intracellular osmolality are some other metabolic disorders that might cause a seizure. Drug toxicity has also been observed as another factor leading to seizures as some drugs or toxins cause indirect effects on brain perfusion, oxygenation, or metabolic disturbances which all may lead to a seizure. Another important factor is genes. There are several elements that lead to brain development. Genes also play a pivotal role in it. The functioning of our brain can be affected by a mutation in some of these genes due to brain malformations that might result in epilepsy [5].

 

Progression of Epilepsy 

The prime etiological factors of epilepsy can be narrowed into precipitation factors and predisposing factors. The former triggers an epileptic response when a patient is exposed to loud noises or bright lights, while the latter depends upon the family history of the patient. These factors lead to altered integrity of the neuron in the epileptogenic focus causing hyper-excitability state of the neurons in the same focus. This leads to high voltage electric discharge causing partial depolarization and partial stimulation of the neurotransmitter molecules, resulting in an imbalance release of excitatory and inhibitory neurotransmitters, ultimately causing an abnormal spontaneous spread of electrical discharge. This aberrated activity in the brain subsequently results in hyper-excitability of neurons in the brainstem leading to a disruption in the functioning of the medulla, pons, and midbrain. This clinical manifestation of abnormal, recurrent, sudden electrical discharge from the brain leads to altered behavior by an individual with or without motor activity [6].

 

Diagnostic Evaluation

Diagnosis of epilepsy can be done in a number of ways. Depending upon several factors, the physician might suggest some tests to diagnose epilepsy and also to determine the cause of seizures based upon the patients’ signs and symptoms as well as after studying the patients’ medical history. Neurological examinations are one way to carry out this evaluation. It includes the examination of various aspects such as behavior, mental functioning, and motor abilities, which help in the diagnosis and determination of the type of epilepsy. Another way is through blood tests. A blood sample is taken to check for the signs of infections or genetic conditions, if any, or any other potential condition that might be linked with the seizures [7].

In addition to these, to be able to detect any peculiarities, the physician is most likely to suggest neuroimaging. Electroencephalogram (EEG) is the most common test used in the diagnosis of epilepsy. In this test, electrodes and wires are attached to the head with the help of a substance called Ten20 paste. These electrodes detect the brain waves and the EEG machine first amplifies the signals and then records them. In an alternate scenario, a variation of an EEG called a high-density EEG can sometimes be proposed to determine the exact areas of the brain that are being affected by seizures.  Other common techniques are computerized tomography (CT scan) and magnetic resonance imaging (MRI). In a CT scan, an x-ray tube rotates around the patient to obtain cross-sectional images of the brain by shooting narrow beams of x-rays through the body. CT scans can capture all the abnormalities within the brain such as tumors, bleeding, or cysts that might be responsible for causing seizures in the patient. MRI employs powerful magnets and radio waves which produce a strong magnetic field to create a more detailed view of the brain. Another technique is by using small amounts of low-dose radioactive material injected in the vein that will help visualize the active areas of the brain and detect any abnormality. This technique is called Positron Emission Tomography (PET).  Sometimes, a single-photon emission computerized tomography (SPECT) is also used primarily in the cases when an MRI or EEG fails to locate the exact location in the brain of the origin of the seizures [4][8].

Moreover, the physician might employ other tests such as a neuropsychological test and the Wada test to evaluate the thinking, memory, and speech skills of the patient. The neurological test results help the physicians estimate which areas of the patients’ brains are troubled whereas the Wada test can help in the evaluation of the significance of each side of the brain in accordance to the language and memory functions. The data from this test determines the approach which is most likely to address seizures while preserving the other areas such as speech and memory associated with the brain.

 

Treatment Approaches

Conventionally known as a highly treatable disorder, epilepsy does have a variety of treatment options available for the patients. These are segregated and then selected based on the most efficient treatment available as well as on the patient requirement. 

The traditional treatment option is through medication.  About 70% of patients can gain seizure freedom through medication alone. Various types of antiepileptic drugs are available that work accordingly with their respective method. There are three methods for the mechanism of action of the drugs, the first being the blockage of the Na+ channel, prolongation of their inactive state, and lastly delaying their recovery.  The drugs used for this method are Phenytoin, Carbamazepine, and Lamotrigine, etc. Another method is through the blockage of low threshold Ca2+ current in the thalamic neurons. This can be achieved through the use of Ethosuximide. The third way is by enhancing GABA mediated inhibition. Now for this different drugs are used which serve different purposes. For example, Benzodiazepine is suitable for acting upon GABA receptors whereas Valproic Acid is used for the inhibition of GABA metabolism [6].

30% of people, or  1 out of 3 patients worldwide have drug-resistant epilepsy.  A person has drug-resistant epilepsy if they fail to achieve seizure freedom after two trials of antiepileptic medications. Under such circumstances, surgical resection and implantation of neurostimulation devices are considered. Surgical resection has been found to exhibit a reduced seizure burden in focal epilepsy. It is generally safe with 1.5% to <5% major medical complications. The most common medical complication is a minor visual field defect which is associated with temporal lobe resection. Patients with clear unilateral mesial-temporal seizures have a higher cure rate with surgery, and resection is more efficient than pharmacological therapy/treatment. The patients diagnosed with neocortical temporal or extratemporal seizures may receive resection or laser ablation provided that the seizure onset does not overlap with the eloquent cortex identified by functional mapping.  In the case of genetic generalized epilepsy, resection is never considered as an option. However, lennox-gastaut syndrome type epilepsy patients may undergo corpus callosotomy for palliative treatment which may alleviate atonic seizures [9].

For non-surgical candidates, neurostimulation devices can be considered. There are three types of neurostimulation devices that are currently available. Vagus nerve stimulator (VNS) is an open-loop system consisting of a generator in the chest wall and an electrode appliance stimulation to the vagus nerve consistently at a fixed frequency. Focal and generalized epilepsy including genetic generalized epilepsy patients has benefited the most from VNS. Patients may stop a seizure at the onset by swiping a magnet over the generator thereby applying a larger current. VNS can detect ictal tachycardia and dispense higher current as well. The responsive neurostimulator (RNS), which was approved in 2013 and is currently only available in the US, is a closed-loop system with a generator in the skull and intracranial electrodes for detecting seizure onsets and treating with stimulation before the patient is affected. A magnet is swiped over the generator to record seizures. RNS is not compatible with MRI, unlike VNS.  Deep Brain Stimulation (DBS) is an open-loop system that consists of a generator in the chest wall with two leads targeting the anterior nucleus of the thalamus. DBS has been shown to be safe and effective in adult patients with focal epilepsy. Patients can intensify stimulation, identify seizures, and turn the device on/off with their own programmer.  A fourth device called external Trigeminal Nerve Stimulation (eTNS) is under clinical trials in the US. It has demonstrated promising results after Phase-II trials. It has been approved in Europe while the approval of the United States is still pending [9]. Sometimes, for drug-resistant epilepsy patients, medically managed diet therapies like DASH diet are also suggested.

 

Conclusion

The third most common neurodegenerative disorder in the world, epilepsy was derived from the Greek word “epilepsia” which means “to seize”. This term was coined by Hippocrates. It is estimated that about 50 million people across the globe are suffering from epilepsy today. While the death rate of epileptic patients remains relatively low, about 5 million people are diagnosed with epilepsy every year.

Epilepsy is a disorder in which the nerve cell activity in the brain is disturbed resulting in seizures. The symptoms majorly depend on the site of origin and so do the treatment approaches. Hence it is important to identify the site of origin and provide the appropriate treatment without disturbing the other parts of the brain. The modern diagnostic techniques have enabled the physicians to lateralize and localize the seizure site and have made it possible to detect any abnormality or peculiarity within the brain.  The current treatment approaches include symptomatic therapies, surgeries, neuronal implants, and palliative care. The article summarizes all the historical developments, common etiology, gradual epilepsy progression, and treatment strategies including neurostimulation devices which have high possibilities to improve epileptic patient care in the current scenario.


References


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Shivangi Chaturvedi

Shivangi Chaturvedi


An enthusiastic undergraduate student pursuing Pharmaceutical Sciences, with a record of academic and extracurricular achievements in the area of neurocognitive research & studies. I am motivated to learn and grow in Neurological research and gain real world research experience in my near future.