Introduction to the clinical problem

Epilepsy is defined as two or more unprovoked seizures resulting from the imbalance of the brain’s electrical rhythm. “Normally, the brain continuously generates tiny electrical impulses in an orderly pattern”[1]. However, in seizures, the pattern is “disrupted by sudden and synchronized bursts of electrical energy that may briefly affect consciousness, movements, or sensations” [2]. Epilepsy can affect anyone at any age. It is not targeted to a particular demographic. However, the chances of being affected with epilepsy are higher in children born to epileptic parents; 2.8 percent chance for someone with epileptic parents and only a 0.5 percent chance for the general population[3].

When a person is clinically diagnosed with epilepsy, their top three reasons for diagnosis are symptomatic, idiopathic, or unclassified. A study about the clinical diagnosis of epilepsy was performed with 100 residents indicating the percent distributions for different reasons for admitting patients. The top three categories for clinical diagnosis of epilepsy include: symptomatic (39.1%), idiopathic (38.6), and unclassified (22.3%). It is alarming to see the percent distribution for unclassified diagnoses is unusually high. Symptomatic diagnoses have three subcategories: toxemic exogenous, toxemic endogenous, and disorders due to definite brain disease. Toxemic exogenous is caused by an external origin or external condition which includes poisoning from alcohol or lead. However, toxemic endogenous is caused by an internal origin or internal condition including renal disorders, pregnancy, puerperal disorders, endocrinopathic disorders, and metabolic disorders. An idiopathic diagnosis indicates that it is due to psychogenic factors which originate in the mind. Worldwide, there are about 5 million epilepsy patients per year [1]. Particularly in the U.S., it was found that 1.2% of the population (3.4 million patients: 3 million adults and 470,000 children) was reported with active epilepsy [4].

Additionally, epilepsy can be characterized according to the region of the brain it is associated with. Epilepsy can affect the temporal lobe, parietal lobe, and occipital lobe. The temporal lobes are the most commonly affected areas of the brain that give rise to epilepsy. “The mesial portion (middle) of both temporal lobes is very important in epilepsy — it is frequently the source of seizures and can be prone to damage or scarring”[11]. Epilepsy can also originate in the parietal lobe and is associated with “sensory disturbances like heat, numbness, electrical sensations, weakness, dizziness, hallucinations, distortions of space and other symptoms”[11]. Seizures beginning in the occipital lobe are rare. Seizures originating in this lobe can cause a person to experience “flashing bright lights or other visual changes on the left side of his or her visual field (if occurring in the right cortex), or on the right side (if occurring in the left cortex)”[11].

The current standard of care for epilepsy includes anticonvulsant medications, nerve stimulation, or surgery. Anti-epileptic also known as an anticonvulsant medication is generally prescribed to patients with epilepsy. However, it can be ineffective for some patients. Therefore, vagus nerve stimulation is an alternative treatment that they can use to reduce the effects of epilepsy. Some doctors prescribe a ketogenic diet to help manage epilepsy for patients who have not improved on medicine alone. If none of these treatments succeed, then surgery is an option [5].

Vagus nerve stimulation is an emerging treatment that is a better alternative to anticonvulsants. “Clinically, the typical stimulation method involves two helical electrodes wrapped around the cervical branch of the nerve”[6]. In a particular study, the activation thresholds for each type of stimulation were determined using the Hering-Breuer (HB) reflex, which is a biomarker for vagus nerve stimulation. It was found that only a certain type of stimulation was able to activate the HB reflex, and that it did not fall under clinically relevant parameters. Moreover, “no activation of the HB reflex was observed with taVNS, revealing a clear difference between the cervical and auricular branches of the vagus nerve”[6].The limitation of this treatment now is that it is hard to fabricate, and implant, and it is also invasive. It is an alternative to medication but still not as effective as surgery.

In Europe, “one hundred eighty-six different tools are in use with moderate agreement depending on the cognitive domain to be assessed”[7]. There is high variability with regard to indications, protocols, and paradigms for the assessment of hemispheric language dominance. There are alternative new treatments like using anti-depressants in epilepsy treatment. This includes selective serotonin reuptake inhibitors (SSRIs) which can reduce seizure frequency in humans. “A careful review of preclinical studies reveals that SSRIs appear to have region-specific and seizure subtype-specific effects, with models of chronic partial epilepsy being more likely to respond than models of acute generalized seizures”[8].

Lamotrigine encapsulated intranasal nanoliposome formulation is another epilepsy treatment that was recently discovered. “The formulation of the LTGNLs was prepared using thin film hydration and rehydration method using the phospholipon 90 G, cholesterol, and tween 80 as main ingredients. The nanoliposomes were optimized by Plucket Burman design (PBD) and response surface methodology (RSM) optimization techniques”[9]. Delivery of necessary chemicals to the brain can aid in normalizing the electrical pattern of the brain and additionally prevent seizures.

Nerve stimulation in other regions of the brain is also a possible treatment. “Low-frequency stimulation in the anterior nucleus of the thalamus alleviates kainate-induced chronic epilepsy and modulates the hippocampal EEG rhythm”[10]. This particular study found that LFS (1Hz, 100μs, 300μA), but not HFS (100Hz, 100μs, 30μA), in bilateral ANT significantly decreased the frequency of spontaneous recurrent seizures, either non-convulsive focal seizures or tonic-clonic generalized seizures.[10]

The limitations of the current standard of care include the lack of consideration of patients with pre-existing conditions like affective problems. Epilepsy surgery can be associated with cognitive decline. There are many side effects that accompany temporal lobe surgery like “up to 45% may experience a decline in memory”[7]. Patients with cognitive problems and affective problems (depression, anxiety, ADHD, autism) should be taken into special consideration before assigning treatment plans. “Affective problems are seen in up to 50% of surgical candidates and—similar to cognitive and behavioral problems—in part result from epilepsy and its treatment, and in part may share the same underlying pathophysiology with epilepsy”[7].