Continuing Education Activity

Temporal lobe epilepsy is the commonest seizure disorder and affects approximately fifty million people worldwide. The primary objective of this activity is to review the epidemiology, pathophysiology, diagnosis, and management of temporal lobe epilepsy. Also, this activity aims to highlight the role of interprofessional care, including neurology, neurosurgery, psychiatry, and epilepsy specialty nurses, in improving the health outcome and quality of life in individuals with this condition.

Objectives:

• Review the etiology and epidemiology of temporal lobe epilepsy.
• Describe some of the common history and physical findings associated with temporal lobe epilepsy.
• Identify treatment options available to individuals with epilepsy.
• Summarize interprofessional strategies to allow for adequate continuity of care, continual surveillance for complications of illness and/or management, and timely therapeutic interventions when necessary.

Introduction

Epilepsy affects about seventy million of the global population and is a chronic, debilitating condition,[1] with the vast majority of these cases originating in the temporal lobe. Furthermore, epilepsy of the temporal lobe can further subdivide into two categories based on the anatomical origin of epileptic focus:

• Mesial Temporal Lobe Epilepsy (MTLE): Involving the anatomy of the innermost structure of the temporal lobe, including the hippocampus, parahippocampal gyrus, and amygdala; this is the most common form of temporal lobe seizures and is usually secondary to a pathological process known as hippocampal sclerosis (HS).
• Lateral Temporal Lobe Epilepsy (LTLE): Also referred to as neocortical temporal lobe seizures.  These are very rare and most commonly secondary to genetic or acquired structural/anatomical lesions.

The impact of epilepsy leads to a decrease in quality-of-life indices, shortened life-expectancy, and by extension, bears a significant economic impact for the individual and society.[2][3]

Etiology

The etiology of temporal lobe seizures is extensive. The most common causes are:

1. Hippocampal sclerosis
2. Infections
3. Tumors
4. Traumatic brain injury
5. Vascular anomalies
6. Genetic
7. Cryptogenic

MTLE is the most common form of epilepsy and is most commonly due to a neurodegenerative process known as hippocampal sclerosis (HS) found in the majority of patients diagnosed with this condition, upon histological evaluation.[4][5] This entity was first identified by Sommer and Bratz in the late 19th century and had the name Ammon’s horn sclerosis.[6] Aberrant neurological conduction, primarily due to the overactivity of stimulatory neurotransmitters such as glutamate or under activity of inhibitory neurotransmitters such as gamma-aminobutyric acid (GABA) with a primary focus in the temporal lobe results in epileptogenesis. It has been well established that the presence and degree of HS is a predictor of post-surgical outcome, with the presence of HS being a better prognostic indicator. Early works by Wyler established a grading scale based on semiquantitative measurements of from no HS (Wyler 0) to severe HS (Wyler 4). The work by Watson added one more tier to this grading system. However, the system of grading established by Wyler has limitations, as it requires analysis of all parts of the hippocampus to determine a reliable score, which is not always possible due to the resection procedure.[7] The International League Against Epilepsy (ILAE) utilized a task force review to classify HS via an easily accessible, semi-quantitative, histopathological analysis of hippocampal cell loss. The ILAE determined three types of HS of varying severity, which should aid in determining the post-surgical outcome and the likelihood of seizure control. An additional fourth subtype with gliosis only has also been characterized.[8]

The three types of HS, as classified by the ILAE, are as follows:

1. HS ILAE type 1 - associated with significant neuronal cell loss and gliosis, mostly in CA1 and CA4 hippocampal regions. It has an association with a history of precipitating injuries in pediatric populations with early seizure onset. It also correlates with a better post-surgical prognosis.
2. HS ILAE type 2 - A form with more pronounced cell loss and gliosis in CA1 hippocampal regions. Less studied but may be associated with a less favorable post-surgical prognosis.
3. HS ILAE type 3 - This is with more pronounced cell loss and gliosis in CA4 hippocampal regions. As with type 2, less studied and may also be associated with a less favorable outcome.
4.  No-HS - with gliosis only, often associated with a less favorable prognosis.

Although about 10 to 15 percent of children who develop febrile seizures progress to a diagnosis of epilepsy,  there is no compelling evidence of causality between a history of febrile seizures and the development of temporal lobe epilepsy. What is evident, however, is the association of lesions in anatomical correlates on neuroimaging, such as mesial temporal lobe sclerosis, in the pediatric population, and the development of temporal lobe epilepsy.[9]

Epidemiology

Temporal lobe epilepsy is usually diagnosed in the first two decades of life, and has no sexual predilection, although females may experience catamenial seizures. Obtaining a reliable epidemiological evaluation of the frequency of epilepsy, in general, has been historically challenging, due to difficulty with methodological ascertainment. One fundamental challenge arises as a result of various modifications made to the definition of epilepsy by the ILAE since the first classification.  Additionally, with regards to the diagnosis of temporal lobe seizures, diagnostic accuracy relies on the use of electroencephalography (EEG) and imaging studies, for which the accuracy is subject to the level of evaluator expertise, as well as the limitation to access to these resources on a global spectrum.[7] There is limited epidemiology research conducted to date, with variations of the incidence and prevalence occurring depending on the selection criteria used for recruitment and assessment. What is evident from these studies, however, is the higher incidence of mesial temporal lobe seizures lead to a referral to surgical centers indicating the often refractory nature of lesions in this anatomical region.[1]

Approximately 60 percent of all forms of epilepsy are focal in origin, with the majority originating in the temporal lobe. About 48 to 56 percent of these cases occur bilaterally.[10] A significant percentage of cases of MTLE are refractory to standard anti-epileptic drug (AED) treatment and should be considered in individuals who continue to experience epileptic seizures for greater than 1 year with the concomitant use of two or more AEDs, should be subsequently referred for surgical evaluation.

Pathophysiology

Being the earliest discovered, and most common pathological finding on the autopsy of patients with temporal lobe epilepsy,[11] hippocampal sclerosis has been the most examined to date. As the name suggests, the primary pathology in this condition occurs in the hippocampus, with neuronal loss, or atrophy in the hilar regions, predominantly localized to the CA1, CA3, C4, and dentate gyrus, with CA2 sparing. Expansion of the normally dense granule cell layer, mossy fiber sprouting, and gliosis being some common findings on pathological specimens. It should be noted, however, that hippocampal sclerosis has a variety of pathological subtypes.[12]

As noted, temporal lobe epilepsies arise through a myriad of etiologies, regardless of the focus of epileptogenic activity. For simplicity, the lateral temporal lobe epilepsies fall into categories as either lesional or non-lesional. Lesional causes are often secondary to anatomical aberrancies. However, the lateral temporal lobe epilepsies have been a poorly studied group to date. Recent studies reveal a significant number of cases clustered in families or secondary to idiopathic genetic mutations.[13] There has also been evidence regarding the role of astrocytes in the pathogenesis of epilepsy as well as interconnected epileptic networks.[14][15][16][17]

History and Physical

Temporal lobe epilepsy characteristically presents with seizure activity originating in either the medial or lateral temporal lobes. The seizures can either be focal aware seizures, focal seizures with impaired awareness, and there can also be seizure activity which originates in the temporal lobe but extends to involve both cerebral hemispheres, commonly manifesting as focal to bilateral tonic-clonic seizures. Chronic memory impairment is a common finding in individuals with temporal lobe epilepsy.[18]

Symptoms of temporal lobe epilepsy include the following: 

1. Focal aware seizures: classically referred to as "auras," these phenomena include special sensory symptoms such as occurring in auditory, olfactory, gustatory, and visceral systems. They may also manifest with autonomic, somatosensory, and cognitive events such as "deja vu," and "jamais vu." Emotional symptoms, such as fear or anxiety, are also possible.
2. Focal impaired awareness seizures: sometimes, a focal aware seizure may progress to a loss of consciousness. During this progression, the patient may display a motionless stare, dilated pupils, and automatisms such as in the facial-oral musculature or unilateral dystonic limb posturing may present.
3. Focal seizures may extend to involve both cerebral hemispheres and frequently manifest with bilateral tonic-clonic convulsions.
4. Both (2) and (3) above may be associated with a postictal period, which may manifest with confusion, aphasia, and/or amnesia.

Inter-ictal symptoms are non-specific in the majority of cases. Occasionally, patients may manifest with a change in the prosody of speech and flattening of the contralateral nasolabial fold with emotional incitement.[19][20]

Evaluation

Neuro-imaging and EEG are valuable in the evaluation of the patient with suspected temporal lobe epilepsy. Since seizures are a relatively transient and rare event for the majority of individuals affected by epilepsy, the ability to perform inter-ictal diagnostic assessments is vital.  

EEG should be performed in all individuals with suspected temporal lobe epilepsy, as it can assist in the localization of epileptic focus, and potentially elucidate possible epileptic networks.[15][21]

An ictal EEG recording of a rhythmic 5 to 7 Hz theta-wave frequency, with peak recordings in sphenoidal and basal temporal electrodes on the ipsilateral side to epileptic focus, is diagnostic. Interictal EEG assessment may be remarkable for spike-and-wave or sharp and slow complexes, usually located in the anterior temporal region, or basal temporal electrodes. Differentiating between MTLE and LTLE by EEG is difficult as the waveforms are similar.

Sometimes a patient with TLE may have a normal initial EEG; tools such as sleep-deprivation and video EEG telemetry may help in ceasing the diagnosis. Also, if there is discordance between the scalp EEG, and clinical or other data, the placement of intracranial electrodes could assist in identifying epileptogenic focus before surgery (reference).

Neuroimaging is vital for the identification of organic or structural anomalies, which may precipitate temporal lobe seizures, such as vascular malformations, tumors, and hippocampal sclerosis. Computed tomogram (CT) scan is routinely used in the ambulatory evaluation but provides limited sensitivity when compared to higher-resolution imaging modalities, such as magnetic resonance imaging (MRI), which is the primary method of choice. MRI is also vital in the pre-surgical assessment of individuals with refractory temporal lobe epilepsy; with mesial temporal lobe epilepsy with hippocampal sclerosis being the most common finding in these cases, key findings on MRI include a reduction in hippocampal volume and an increased signal intensity on T2 imaging in the hippocampus-FLAIR may be used to enhance imaging. T1 imaging may visualize grey-white matter contrast and provide enhanced neuroanatomical detail of the hippocampus. The majority of cases of hippocampal sclerosis are bilateral in nature, which may lead to difficulty with diagnosis by conventional imaging modalities; volumetric analysis may help to identify these occurrences.[6] There are some limitations to the use of MRI, such as being subjective to the interpreter's expertise. Approximately 57 percent of focal epileptogenic lesions are missed on standard MRI, making a referral to specialty epileptic clinic beneficial, for evaluation and accessibility to functional neuroimaging modalities.[22]

A functional imaging positron emission tomography (PET) scan or magnetic resonance spectroscopy (MRS) may also be an option in select unconfirmed or inconclusive cases.[6]

For individuals under evaluation for surgical intervention, adequate localization of epileptic focus with the preservation of unaffected areas is essential for optimizing post-surgical outcomes. Sometimes epileptic foci may not be apparent on MRI, and additional imaging modalities may be necessary interventions. The PET scan is a useful intervention in such cases, as it can be to identify epileptogenic zones interictally, independently, or in conjunction with CT/MRI for localization. An interictal PET scan with FDG labeling may reveal hypoperfusion in epileptogenic zones.

SPECT scanning is also a useful modality as it can identify epileptic focus in approximately 80 to 90% of cases evaluated; however, diagnostic accuracy is limited in interictal evaluations. Ictal findings with the use of 99mTc-HMPAO (hexamethyl propylene amine oxime) (within 30 seconds of seizure onset) show hyper-perfusion of the medial and/or lateral temporal lobe. Interictal-ictal SPECT subtraction may add enhanced localization value.

Magnetic encephalography (MEG) usually measures the magnetic field generated from interictal spikes and may be used in conjunction with MRI to obtain 3-dimensional magnetic source imaging, and useful in patients who require structural evaluation without the exposure to contrast agents. There are limitations, with this modality as it relies on interictal characterization, and is less informative than ictal EEG recordings.

Traditionally, the intra-carotid amobarbital test (WADA test or IAP) has been used in the pre-surgical evaluation of temporal lobe epilepsy to localize the verbal and visuospatial memory centers in the temporal lobe, as well as extra-temporally, and to assist with selective resection. This test is, however, an invasive procedure, and recently, researchers have made functional MRI (fMRI) comparisons to the WADA test as a less invasive measure. Limited class I and class II evidence shows significant concordance between IAP and WADA test findings and supports the ability of fMRI to assess post-surgical outcomes in language centers. 

Treatment / Management

Since cumulative seizure time is directly related to neurocognitive decline, reducing seizure frequency, and ideally, achieving seizure control is essential. The impact of epilepsy, as well as its management, have serious implications on the quality of life of the patient and should be taken into consideration.

Upon diagnosis of temporal lobe epilepsy, initial management should be pharmacological intervention with one of a variety of AEDs. Older AEDs such as phenytoin, valproate, carbamazepine, and phenobarbital, are equal in efficacy to newer AEDs like lamotrigine, gabapentin, or levetiracetam, but correlate with a higher rate of adverse effects such as hepatotoxicity. Clinicians should avoid valproate and topiramate if possible, and lamotrigine and may consider levetiracetam, due to clinical evidence of higher rates of favorable outcomes in pregnancy.[23][24] Women of childbearing age should also understand the potential teratogenicity with the use of AEDs in the first trimester. 

About one-third of patients with temporal lobe epilepsy do not have a resolution of seizures after initiation of AEDs.[25]  The definition of refractory epilepsy has no objective definition but gets determined through the assessment of various domains that influence the prognosis of the condition such a frequency and severity of seizures, the number of AED failures and adverse effects of AEDs used, and the subsequent impact on the livelihood of the individual with epilepsy.[26] Seizure remission, or tractable seizures, may be considered as a period of greater than 6 months to 2 years of seizure freedom.[26] Surgery is one option for individuals with refractory temporal lobe epilepsy and may provide up to an 80 percent remission rate in individuals with HS.[5] Evidence suggests the superiority of the addition of temporal lobe surgery over AEDs alone, for seizure control in refractory cases.[27][28] Early surgical evaluation and intervention, when indicated, may be beneficial through improvements in quality of life indices as well as evidence suggesting an improvement in intelligence quotient (IQ) scores, and overall lifetime medical cost with pediatric surgical interventions.[29]

The two most commonly performed surgical interventions anterior temporal lobectomy (ATL), involving the resection of the anterior temporal lobe, amygdala, hippocampus, and parahippocampal gyrus, as well as selective amygdalohippocampectomy (AHP), which targets the mesial structures specifically, preserving much of the cortical anatomy.[30] A meta-analysis comparing the one-year seizure freedom for ATL and AHP, as well as comparing each of these interventions to AEDs revealed no significant difference between the two procedures, but significant improvement in seizure freedom when compared to AEDs.[28] With regards to ATL, there are two general techniques employed: the traditional, or standard anterior temporal lobectomy, as well as anteromedial temporal resection.

In the standard anterior temporal lobectomy, a posterior cortical incision is made at the level of the lateral temporal gyri beginning around 5.5 cm from the temporal tip in the nondominant hemisphere and 4.5 cm from the temporal tip in the dominant hemisphere at the level of second temporal gyrus. This incision is slanted to avoid the primary auditory cortex in the first temporal gyrus. In comparison, the anteromedial temporal resection technique was developed to preserve more function of the lateral temporal lobe, in addition to aid in the access of mesial temporal structures. This procedure removes around 5 to 6 cm of the temporal lobe. The cortical incision is initiated at about 3 to 3.5 cm from the temporal tip and continued inferiorly towards the third temporal gyrus, with sparing of the auditory cortex in the first temporal gyrus. The mesial structures are subsequently removed using an ultrasound aspirator.

There is inconclusive evidence that a more selective approach may improve neurocognitive outcomes.[30] The choice of open surgery versus selective interventions should be under the guidance by the challenges provided by the lesion, either locational or intrinsic characteristics. Included in more selective and less invasive approaches to anatomical correction for temporal lobe epilepsy are stereotactic radiosurgery as well as stereotactic laser ablation. These interventions are also valuable in lesional sites that are difficult or too risky to access via open surgical procedures. Recent evidence suggests that stereotactic radiosurgery provided similar results as open surgery with regards to seizure remission rates and neuropsychological prognosis, but has an extensive latency period until maximum therapeutic benefits, needed for corrective radio-surgical lesion formation. It also appears to have limited benefits in individuals with lesions secondary to arteriovenous malformations, as it may be associated with rebleeding. Stereotactic laser ablation is a more recent intervention but has shown promising results with regards to therapeutic outcomes. The use of MRI thermometry minimizes thermal damage to unaffected structures adjacent to the lesion as compared to radiofrequency ablation.

For individuals in whom surgery is contraindicated, other options are available for consideration.[31] Neurostimulation is one such option, with vagus nerve stimulation (VNS) and responsive neurostimulation (RNS) being some modalities employed in the United States.[32][33] Deep brain stimulation has been a new tool used to treat a variety of neurocognitive and neuromotor disorders but is not FDA approved at the time of this article, for the management of refractory epilepsy in the United States.[34]

The use of ketogenic dieting may also be beneficial at reducing ictal frequency.[35]

Differential Diagnosis

The differential diagnosis of temporal lobe epilepsy include the following:

1. Other forms of focal onset epilepsy (i.e., absence, frontal lobe, parietal lobe)
2. Migraine 
3. Psychiatric disorders (i.e. panic disorder, psychotic disorders)
4. Nonepileptic seizures
5. Syncope

Prognosis

While the majority of patients affected by epilepsy can achieve successful seizure control with one or a combination of AEDs, temporal lobe epilepsy is often refractory to neuroprotective agents.[25] About 75 percent of patients with MTLE do not achieve significant seizure control with medical treatment, with about 75 percent obtaining seizure freedom following surgical intervention.[36] Of those refractory to AEDs, temporal lobe surgery has been shown to improve the quality of life, mortality, and overall healthcare cost in successful procedural outcomes.[29]

Complications

The risk of irreversible neurocognitive decline increases with the duration and frequency of epilepsy. Quality of life and other psychosocial domains are affected for these individuals.[37][38] Depression, anxiety, memory impairment, and other neurocognitive disorders are resultant comorbidities in this population.[18] Also of concern in the epileptic patient is the adverse side-effects of many AEDs, including hepatotoxicity, teratogenicity, and toxic dermatoses, among others, and surgical complications in those undergoing these procedures.

Sudden unexplained death in epilepsy (SUDEP) is sudden death in an epileptic patient occurring in the absence of status epilepticus and with unknown causes.[39] It has a yearly incidence of around 0.1 percent annually in the epileptic population and is the leading cause of death individuals who are unable to achieve seizure control.[40] Cardio-autonomic or respiratory dysfunction is likely central to the pathogenesis of SUDEP.[41]

Deterrence and Patient Education

Patients should be made aware of the potential complications of epilepsy and educated of the associated benefits and risks of all available therapeutic options. In some states, it is mandatory to report epileptic status to the department of motor vehicles, due to ictal events being a potential risk for motor vehicle accidents.

Enhancing Healthcare Team Outcomes

The management of temporal lobe epilepsy is best with an interprofessional team. Early diagnosis and intervention allow for better outcomes in patients with epilepsy. Anxiety, depression, memory impairment, and cumulative ictal time are some of the variables reducing the quality of life for the individual with epilepsy.[42]

Recent advancements in imaging technology have resulted in improved identification and characterization of epileptic lesions.[43] However, a systematic review assessing the added benefit of using imaging modalities for surgical decision making and cost reduction yielded controversial results.[44]

Expert evaluation and referral to epilepsy centers, where appropriate, provide additional benefit.[22] Surgical evaluation should not be delayed in individuals refractory to AEDs, given the growing evidence identified in Level I and II studies for the improvement in ictal control after surgical intervention in refractory temporal lobe epilepsy.[45]

Effective communication between the health care provider (HCP) and the individual with epilepsy is central to achieving an optimal prognosis. Significant management and outcome variables, such as complications associated with ongoing seizures, potential adverse effects of AEDs, and the benefits and risks of all other therapeutic interventions, should be discussed in a manner that is clear, concise, and considerate of individuals psychosocial and economic status. Educational opportunities, such as one-hour courses offered to clinicians to assist them in how to formulate open-ended questions, and effectively communicate with their patients, help to improve the clinician's communication skills.

Chronic disease management models for epilepsy, aim to maintain quality of care while minimizing healthcare costs; emphasis is on patient education, interprofessional communication-due to the numerous overlap among the specialties, and continuity of care. The provision of educational resources and clinical guidelines to primary care practitioners treating individuals with epilepsy is also of benefit by increasing the skilled knowledge base for the management of this disorder. Epilepsy specialty nurses (ESNs) play vital roles in information gathering, distribution, and counseling, and their skillset should be employed when available. The ability to provide timely interventions for the epilepsy population contributes positively to the outcome of this disorder. Technology has been an efficient modality for the distribution of accurate and up-to-date information for patients and HCPs alike. It also permits for evaluation of patients who are not close to epilepsy centers. However, increasing clinical documentation requirements and shorter consultation sessions may be an inhibitor to adequate information gathering. Level II studies conducted in the United Kingdom indicated benefits with an "open-access model" whereby individuals with epilepsy are provided ease of access to ESNs via telecommunication, leading to a reduction of clinic visits.[46] Furthermore, other Level II studies indicate that a nurse-led approach, using competency frameworks as management objectives, may lead to a reduction in overall healthcare costs.[47]

Given the necessity and use of AEDs in treating the condition, a pharmacist, particularly with pharmacotherapy board certification, can assist with agent selection, checking for potential interactions, and verifying dose and duration, as well as recommending alternative agents in the event of inadequate response.

The examples above with nursing access and pharmaceutical intervention are examples of how an interprofessional team approach optimizes treatment for epilepsy in general and temporal lobe epilepsy in particular, leading to better patient outcomes. [Level V]

It is essential to recognize the relationship between psychiatric disorders and temporal lobe epilepsy. Neurologist should be trained in screening for anxiety and depression, and provided appropriate interventions; the use of screening questionnaires such as the Columbia Suicide Severity Rating Scale (CSSRS) and the Neurological Disorders Depression Inventory for Epilepsy (NDDIE), as well as the Montreal Cognitive Assessment Test (MoCA) are effective screening tools for  psychiatric evaluation, and clinicians should incorporate them when indicated.

Epilepsy support groups and other social interventions may also provide some benefit to the individual with epilepsy due to evidence for improvement in cognitive function in structured environments.[48]

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Disclosure: William McIntosh declares no relevant financial relationships with ineligible companies.

Disclosure: Joe Das declares no relevant financial relationships with ineligible companies.