Epilepsy is a seizure disorder where the patient suffers from recurrent seizure episodes. It is defined as having more than one unprovoked seizure during a 24 hour period (). Seizures are caused by the abnormal electrical activity of neurons in a region of the brain. The clinical phenotype of the disorder is mainly determined by the functional region affected and the pattern of spread of the abnormal electrical activity throughout the brain (Duncan, Shorvon and Fish 1996). Among the range of clinical manifestations of epilepsy, including postictal confusion, automatisms, motor activity and auras, the most common is convulsion which around 60% of patients suffer from (Shorvon, Perucca and Engel 2016).
Epileptic seizures can be focal or generalized, based on to which extent the brain is affected. Focal seizures affect one cerebral hemisphere and the patient can either remain conscious or have impaired consciousness, called simple and complex focal seizures, respectively. Focal seizures are further subcategorized based on the seizure focus (). Generalized seizures affect both hemispheres and the patients lose consciousness for either a brief or long period of time. A focal seizure can spread and develop into a generalized seizure and these are called secondary generalized seizures.
A seizure is caused by overactivity of a cluster of neurons, where electrical signals in a particular region fire simultaneously, leading to the clinical features associated with epilepsy. This region is often referred to as the seizure focus. The electrical activity is either caused by overactivation of excitatory signals or by hypoactivation of inhibitory signals, both leading to overstimulation of excitatory receptors (). An example for this is glutamate and GABA. Glutamate is the main excitatory neurotransmitter in the brain and NMDA is its most abundant receptor. Rapid or prolonged activation of NMDA by binding glutamate can cause prolonged depolarization of the neuron. Conversely, GABA, the main inhibitory neurotransmitter, causes inhibition of action potentials through hyperpolarization of the membrane potential when it binds to the GABA receptor. Dysfunctional GABA receptors cannot bind GABA, so signals cannot be inhibited, which subsequently causes overactivation of the neurons ().
Frontal lobe epilepsy (FLE) is an epileptic disorder arising in the frontal lobe. It accounts for 20% of epilepsy-related surgical resections, second only to temporal lobe epilepsy (TLE) (), and affects 1-2% of epileptic patients(). The seizures are simple or complex focal seizures and it is the most common cause of secondary generalized seizures (). The onset of FLE can be anywhere from infancy to the sixth decade, although the majority of cases start in the first or second decade of life and persist throughout adulthood (Scheffer et al).
FLE has a variety of etiologies, however, the cause is undetermined for about 50% of the patients (). The most common determined causes are head trauma, by stroke or mechanical injury and brain tumours. Others causes are abnormal brain tissue, abnormal brain vasculature, previous infections and neuroinflammation. A few families have been identified with a genetic cause for FLE with autosomal dominant inheritance, called autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE)(Scheffer et al 1995). The most commonly identified mutations are in the CHRNA4 and CHRNB2 genes, and possibly the CHRNA2 gene, encoding for alfa and beta subunits for nicotinic acetylcholine receptors (nAChRs) (Conti et al 2015). There are also other unidentified genes causing ADNFLE (Becchetti et al). nAChRs bind acetylcholine which causes an excitatory activation. In ADNFLE, this binding…..In general, inherited FLE is rare, however, it is a good model for studying sporadic FLE cases as it has similar clinical and EEG features (Conti et al 2015).
FLE episodes are primarily brief seizures, often lasting for less than 30 seconds and occur in clusters of an average of 6 seizures (Scheffer et al 1995), with or without partial recovery between each seizure. Episodes are often nocturnal, arising straight after falling asleep or right before waking up in the morning (Scheffer et al 1995). There is sudden seizure onset and short or no postictal period. Status epilepticus is a common complication of FLE (Hopkins, Shorvon and Cascino 1995).
Around 90% of patients have a motor manifestation (Oxbury, Duchowny and Polkey, 2000), which correlates with the frontal lobe’s role in motor functions and consciousness is often preserved. Episodes are stereotypical for an individual, but there are variations in the manifestations between patients based on the anatomical origin.
Other FLE features depend on the affected functional region of the frontal lobe. The seizures are therefore subclassified based on the location of the seizure focus into the primary motor cortex, the supplementary motor area, the medial frontal, the dorsolateral cortex, cingulate, orbitofrontal, frontopolar, and the frontal operculum seizures. There are characteristic features for seizures originating in each region, however FLE seizures often spread rapidly from the seizure focus to adjacent cortical regions, causing overlapping features and making a clear distinction difficult (Hopkins, Shorvon and Cascino 1995).
The frontal lobe is involved in motor functions, cognition, behaviour, and arousal, which causes a diverse range of features in FLE. The lobe has different functional regions such as the primary motor cortex, premotor area, frontal eye field, supplementary motor area, prefrontal cortex and the Broca’s area, which cause the features seen in epilepsy when affected by seizure activity.
The motor cortex (consisting of the primary motor and premotor cortices and the supplementary motor area) is the primary region for planning, control and execution of motor movements (). The primary motor cortex (MsI) is involved in contralateral movement control (Johns 2014). It outputs to the brainstem and spinal cord through the corticobulbar and corticospinal tracts, respectively. The premotor cortex, which inputs to the Msl, is responsible for the sequence and preparation of movements.The supplementary motor area (SMA) is involved in the planning of complex movements and coordination of two-handed movements. Seizure involvement of these areas leads to motor movements. Anterior to the motor cortex is the prefrontal cortex which has a primary role in executive and cognitive functions. It is subdivided into further cortices including the orbitofrontal (inhibition of inappropriate behaviour, smell discrimination and working memory), medial (maintenance of emotional state, mood and motivation) and dorsolateral prefrontal cortex (organisation, regulation and planning movements from sensory input). Involvement of these regions can for example cause auras and problems with awareness. The Broca’s area and the frontal eye fields are also part of the prefrontal cortex (). These are responsible for speech production and control of voluntary eye movement, respectively. When the Broca’s area is affected by seizure activity, speech arrest or vocalization may occur (Hopkins, Shorvon and Cascino 1995). Involvement of the frontal eye field may feature versions of the eyes and head (Zhang et al 2017). The frontal operculum is thought to have a role in speech production, planning behaviour, facial movements, and cognition (). Involvement of this area leads to problems with functions related to the mouth and jaw. The functions of the anterior cingulate cortex includes autonomic functions and attention.
Seizures originating from the Msl manifest with motor activity, usually clonic or myoclonic movement. Jacksonian march may occur in some patients that can trigger another episode of seizures in another area. Patients typically remain conscious during the focal seizure, however secondary generalization is common leading to unconsciousness. Patients may suffer from speech arrest and facial tonic-clonic movements when lower motor cortex are involved, whereas contralateral dystonic posturing may occur when the upper regions of the motor cortex are affected (Hopkins, Shorvon and Cascino 1995).
Supplementary motor area seizures are more complicated in nature (?). Responsiveness is usually intact. Episodes present with motor manifestations, which are unilateral or asymmetrical bilateral tonic posturing, known as the fencing posture, due to the role of the SMA. Postural, focal tonic, with vocalization, speech arrest, and fencing postures (Hopkins, Shorvon and Cascino 1995). These seizures often commence with auras, which is uncommon for other FLE seizures ().
Medial FLE present with very unusual features, which include emotional feelings, vocalization, laughter or crying, viscerosensory symptoms, and repetitive motor activity like pelvic thrusting, pedalling and thrashing. These features are why medial FLE is often misdiagnosed as psychogenic. Dorsolateral FLE seizures are both tonic and clonic. Common manifestations include tonic posturing or movement, contralateral head and eye deviation and speech arrest. Ipsilateral manifestations are rare but possible (Hopkins, Shorvon and Cascino 1995). Seizure focus in the frontal operculum, called an operculum FLE, manifests in facial movements especially related to the mouth and jaw functions without much other motor activity. Patients experience problems with swallowing, salivation, masticulation, and speech arrest. They may also experience feeling fearful, epigastric auras, gustatory hallucinations and autonomic phenomena (Hopkins, Shorvon and Cascino 1995). Cingulate seizures onset with automatisms. Frontopolar seizures have forced thinking or movement, adversive head and eye movement, unconsciousness and possible dystonic clonic movements. Some FLE cases are nonlocalized. These episodes are often brief absence seizures, manifested by intense staring. The EEG shows generalized spikes which is similar to EEG for primary generalized absence seizures. This makes it difficult to differentiate between the two conditions. The seizures may also present as generalized tonic-clonic seizures without an obvious focal onset.
There are key features of FLE that makes it distinguishable from other forms of epilepsy. FLE seizures are brief whereas seizure of other epilepsy disorders often last for 2 minutes. Some epileptic patients can anticipate a seizure due to its gradual onset by experiencing sensory features like auras. This is uncommon in FLE as seizure-onset is sudden (Kotwas et al 2016) and often commence with motor features. Postictal confusion is also a common feature for epilepsy, however this is not the case for FLE where postictal confusion is short or absent (Hopkins, Shorvon and Cascino 1995). Gestural and complex automatisms are characteristically present at onset for orbitofrontal, medial, SMA, cingulate and frontopolar seizures (Hopkins, Shorvon and Cascino 1995). This may also include vocalization, laughing, crying, moaning, or grunting at onset (Scheffer et al 1995), which is why FLE episodes are sometimes viewed as bizarre. Another distinct characteristic of FLE is that seizures occur in clusters, as well as the high frequency of episodes compared to the other epilepsy disorders like TLE (Shorvon et al., 2013). FLE seizures often spread quickly which can further lead to a secondary generalized seizure. This is uncommon for other types of epilepsy. FLE seizures are often a sleep-related.
As discussed, FLE seizures have clinical features that make it unique and distinguishable from seizures originating from other regions such as vocalisation and repetitive movements. Temporal lobe epilepsies are the most common and hence most studied form of epilepsy, making them a good basis for comparison (Duncan, Fish and Shorvon 1996). Three key distinguishing features are:
brief seizure duration: FLE has a characteristic brief seizure duration, which is uncommon for other epilepsy conditions where one seizure usually lasts for 2 minutes
brief postictal phase: following other epileptic episodes, gradual recovery and postictal confusion is common. This is not the case in FLE, which has rarely had postictal confusion and a quick recovery (Hopkins, Shorvon and Cascino 1995).
Clusters of seizures: FLE episodes usually feature in clusters of seizures, which is unusual for other types of epilepsy. FLE is also frequent, which is unusual for other types of epilepsy (Shorvon et al 2013)
Additional unique characteristics of FLE include sudden onset of the seizure (Kotwas et al 2016). Some epileptic patients can anticipate a seizure episode by experiencing sensory features like auras, as the seizure onset is gradual. FLE is also mostly nocturnal and the commonest reason for status epilepticus. Many FLE conditions are refractory, which is why surgical resection of the EZ is not uncommon (Beleza and Pinho 2010).
FLE is often misdiagnosed as parasomnias, paroxysmal movement disorders, and non-epileptic seizure disorders due to their overlapping symptoms (). In addition to the lack of definitive diagnostic tools and the unusual manifestations, the nocturnal aspect is a primary reason why FLE is commonly diagnosed late as well as being misdiagnosed. Often patients themselves are not aware of having seizures. A detailed patient history is therefore the best tool for making an accurate diagnosis.
Almost all antiepileptic medications work well for FLE patients and are taken daily to control seizure activity. Some patients may need combined therapy depending on the severity of their condition. For patients with refractory epilepsy, which is when antiepileptic medications are not sufficient for seizure control, surgical resection of the epileptogenic zone may be performed. Localizing the epileptogenic is therefore important before performing the surgery. However, this procedure is invasive and therefore avoided when possible (Beleza and Pinho 2011). Vagal nerve stimulation is another treatment option, but like surgery, it is invasive.
Conclusion
FLE has characteristic manifestations that make it a unique form of epilepsy. The frontal lobe is further subdivided into its functional regions that have characteristic features when the epileptogenic zone is in that region.