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Mesial Temporal Lobe Epilepsy
Introduction
The temporal lobes are the most common brain region to develop epileptogenicity.[1] Historically, "uncinate fits" were first described by Hughlings Jackson in the 19th Century linking seizures presenting as "dreamy states" to lesions in the uncus of the temporal lobe. In the mid-20th century, the term "psychomotor epilepsy" was introduced by Gibbs and Gibbs to describe the characteristic psychic and emotional semiological findings of patients with seizures arising from the temporal lobes and their associated electrophysiologic features.[2] These experiential phenomena were later studied by Jasper and Penfield using intraoperative stimulation experiments and confirmed to arise from the temporal lobes.[3]
Mesial temporal lobe epilepsy (MTLE) is often discussed as a separate entity because it is quite distinct from its lateral counterpart in terms of etiology, semiology, imaging, and electrophysiologic characteristics. Moreover, the mesial temporal lobes tend to be the site of origin of close to 80% of all TLEs.[4]
Etiology
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Etiology
Most cases of MTLE are sporadic in occurrence, although familial forms are not uncommon.[5] One study showed that as high as one-fifth of the newly diagnosed non-lesional MTLE could have a familial attribute. Research has identified a genetic locus for familial MTLE in a large family with autosomal dominant MTLE phenotype.[6] The familial MTLE cases have been shown to exhibit a complex inheritance pattern and usually do not exhibit mesial temporal sclerosis on imaging.[7]
Hippocampal sclerosis (HS) is the most common histopathological abnormality found in patients with drug-resistant TLE. In a European series of 9523 patients with epilepsy undergoing surgery, HS was identified in 36.4%, long-term epilepsy-associated tumors (LEAT) in 23.6%, and focal cortical dysplasias (FCD) in 19.8%.[8] FCDs classify as malformations of cortical development (MCDs), which also include polymicrogyria, nodular heterotopia, and hamartomas, which are less common pathologies involved with temporal lobe epilepsy. Other less common etiologies include post-infectious (most commonly after HSV encephalitis), vascular malformations, ischemic lesions, inflammatory lesions, and old traumatic encephalomalacia.[9][10]
Epidemiology
There does not seem to be a specific age or sexual predominance to MTLE. Patients usually have normal perinatal history and have normal development. They generally have a normal neurological examination and are cognitively intact. A childhood history of febrile seizures is an important harbinger for the development of MTLE.[11][12] A prospective study performed on 226 children with febrile status epilepticus [FEBSTAT] found evidence of acute hippocampal injury in 9.7% of patients. Subsequently, follow-up MRI of the brain on 14 of these 22 patients showed hippocampal sclerosis in 10 and hippocampal volume loss in 12.[13] Other less important risk factors include head trauma, birth trauma, childhood central nervous system (CNS) infection, and posterior cerebral artery territory infarcts.
Histopathology
Hippocampal sclerosis is histopathologically seen as segmental pyramidal cell loss in CA1, CA3, and CA4 regions, whereas CA2 pyramidal and dentate gyrus granule cells are most seizure resistant.[14] Neuronal cell loss is associated with reactive astrogliosis causing tissue stiffening, which has been traditionally termed as "Ammon's horn sclerosis."[15] Some of the proposed pathomechanisms include disruption of neuronal circuitries, causing aberrant mossy fiber sprouting and molecular rearrangement/plasticity of ion channel and neurotransmitter receptor expression.[16][17] Abnormalities have also been noted in the dentate gyrus in the form of granule cell dispersion.[18] Additionally, variable cell loss is also detectable in adjacent cortical regions, including the subiculum, entorhinal cortex, and amygdala.
Several classification systems have been proposed for HS. The most widely used is the ILAE classification system, which divides HS into three types based on a semi-quantitative survey of segmental cell loss within hippocampal subfields. International League Against Epilepsy (ILAE) type 1 has both CA1 and CA4 loss; ILAE Type 2 has predominant CA1 loss, and ILAE Type 3 has predominant CA4 loss.
Malformations of cortical development represent a wide range of cortical lesions resulting from the derangement of normal developmental processes involving cells implicated in the formation of the cortical mantle.[19] Focal cortical dysplasias (FCDs) represent the most common type of MCDs and characteristically demonstrate disruption of normal cortical lamination by the presence of 'large aberrant neurons' as well as 'grotesque cells' in both cortex and subcortical white matter.[20]
Gangliogliomas and dysembryoplastic neuroepithelial tumor (DNET) is the most frequent long-term epilepsy-associated tumors (LEAT) comprising 65% of brain tumors encountered in patients undergoing epilepsy surgery.[21][22]
History and Physical
Seizure Semiology
The International League Against Epilepsy (ILAE) has recently brought out an updated multilevel classification system for epilepsies to highlight the etiologic basis of the patient’s condition.[23] This update is a reflection of our gain understanding of the underlying mechanisms of epileptogenesis and is crucial in making rational treatment decisions. Based on this revision, patients with MTLE usually are classified as having focal epilepsy and manifest as focal onset seizures with or without impaired awareness.
When there is preserved awareness, the patient can describe the occurrence of unusual sensations known as auras. Auras could be visceral, autonomic, gustatory, or affective symptoms. Patients commonly experience a rising epigastric sensation, nausea, and olfactory and/or gustatory hallucination. Psychic sensations can occur, such as depersonalization (out-of-body feeling), déjà vu (a feeling of familiarity), jamais vu (feeling of unfamiliarity), déjà entendu (hearing familiar sounds), or panoramic visions (a rapid recollection of episodes from the past). Dysphoric or euphoric feelings, fear, terror, anger, and other sensations can also occur. Often, the patients find the aura hard to describe. Autonomic features include piloerection, pallor/flushing, tachycardia, or pupillary dilatation.[24] With the loss of awareness, patients have a behavioral arrest and portray a blank staring facial appearance, which is followed by the development of oro/facial/alimentary automatisms such as lip-smacking, chewing, sucking, or swallowing, which is usually accompanied by ipsilateral gestural automatisms such as repetitive hand movements, picking and/or fidgeting behavior, disrobing and contralateral dystonic posturing of limbs. The presence of speech suggests non-dominant hemispheric seizure onset, but its absence is not a reliable lateralizing finding. Patients commonly have a period of postictal confusion following the episode. Less commonly, episodes may progress to generalized tonic-clonic seizures.
Evaluation
Although the advent of antiepileptic medications has improved the quality of life of patients with epilepsy by reducing seizure frequency, many of the patients with MTLE have a greater tendency to become pharmacoresistant over time. Studies have shown that less than 25% of patients with MTLE remained seizure-free for greater than one year.[25] This data elucidates the importance of non-pharmacological therapies in patients having MTLE. However, most of these non-pharmacological modalities require accurate identification of the epileptogenic zone to provide successful seizure outcomes.
The basis of presurgical evaluation for epilepsy is to identify the epileptogenic zone, which is defined as the minimum amount of cortex that needs to be inactivated/resected/disconnected to render the patient seizure-free.[26] However, the epileptogenic zone is a theoretical construct, and its identification is a matter of careful approximation of all available information sources. These sources include electrophysiologic data obtained from electroencephalography (EEG) and magnetoencephalography (MEG) that have a good temporal resolution and various neuroimaging modalities such as magnetic resonance imaging (MRI,) interictal positron emission tomography (PET), ictal single-photon emission tomography (SPECT), subtracted ictal SPECT co-registered to MRI (SISCOM), and functional MRI that have a good spatial resolution. Neuropsychological assessment is also employed as a part of a presurgical evaluation to evaluate for functional characteristics of the affected epileptogenic region. Such an extensive evaluation can be performed most effectively at a comprehensive epilepsy center with a cohesive team of specialists with training in neurology, neurosurgery, neuroradiology, neuropsychology, neuropathology, and psychiatry liaison services.
High-resolution 3T/7T MRI of the brain with thin cuts obtained through the temporal lobes is a powerful tool to assess subtle structural abnormalities involving the mesial temporal structures. Additional information regarding hippocampal pathology is obtainable with the use of multiple MR modalities such as volumetry, spectroscopy, and Diffusion Tensor Imaging (DTI).[27] Interictal PET looks at hypometabolism and can identify the epileptogenic temporal lobe in up to 70% to 90% of patients with MTLE.[28] On the other hand, ictal SPECT/SISCOM looks at hyperperfusion and is also a useful tool, especially while looking at the origin and spread along the epileptogenic network.[29][30]
The goal of presurgical evaluation for epilepsy surgery is to lateralize and localize the seizure focus accurately; this includes phase I and phase II evaluation:
Phase I evaluation includes the use of non-invasive modalities to determine where the seizure starts; this includes techniques such as video-EEG, MEG, MRI, interictal PET, ictal SPECT/ SISCOM, and neuropsychological assessment. Patients with temporal lobe epilepsy involving the dominant temporal lobe also need functional MRI and/or intracarotid amobarbital/methohexital (Wada) test for language and memory lateralization.
Phase II evaluation includes the use of surgically placed electrodes directly over the brain parenchyma to determine where exactly the seizure is originating. This phase involves the use of invasive techniques such as placement of subdural grids/strips and/or depth electrode placement for electrocorticography (ECoG) and stereo-electroencephalography (SEEG).
Scalp Electroencephalogram
The EEG background in patients with mesial temporal lobe epilepsy is usually normal. There may be periods of intermittent slowing noted in the anterior temporal EEG derivations that become prominent during sleep and hyperventilation and are suggestive of focal cerebral dysfunction. Sometimes the focal slowing can be more robust and manifests as temporal intermittent rhythmic delta activity (TIRDA).[11][4]
In addition to slowing, the classic interictal EEG abnormality in MTLE are spikes or sharp waves which phase reverse over the anterior temporal regions. The dipole orientation of these sharp waves seems to have maximum electronegativity and voltage in the basal temporal derivations (T8/T9; FT8/FT9), and electropositivity distributed widely in the contralateral centro-parietal derivations (C3/C4; P3/P4).[31][32] The sharp waves in the anterior temporal region present in the majority of patients with MTLE. [33] They tend to occur more frequently during drowsiness and early stages of sleep.[34] They become less frequent during REM sleep and are somewhat similar in frequency to that seen during awake periods.
Ictal EEG findings in patients with MTLE are unique when compared to neocortical epilepsy because of its gradual, rhythmic build-up and delayed spread to neighboring brain regions. The seizures that arise from the hippocampus usually spread to the basal temporal regions. Therefore, the use of sphenoidal electrodes can be very useful in picking up the ictal onset in many of the cases with this seizure type. The characteristic pattern seen at the onset of an MTL seizure is a rhythmic theta activity starting in the anterior/anterior-inferior temporal or sphenoidal electrode contacts with gradual spread to the lateral temporal, insular, and frontal regions.[32] An important localizing feature that can sometimes present is the occurrence of diffuse EEG attenuation and cessation of interictal epileptiform discharges (IEDs) at the onset of the seizure.[35] Shortly after the onset, a slower rhythmic theta build-up or organized spiking is noted, which gradually evolves in frequency and amplitude until the seizure spreads to neighboring brain regions followed by spread to the contralateral hemisphere. When the EEG onset precedes the clinical onset, the localization of the seizure onset to the ipsilateral hemisphere is close to 95%.[36] Finally, studies have found that postictal slowing is an important lateralizing feature in up to 70% of the cases.[11][32]
In contrast, an ictal onset with unilateral delta slowing and repetitive interictal spiking is less likely to be arising from the mesial temporal region.[32][37] Also, seizure onset with bilateral rhythmic activity and delayed evolution into a temporal pattern is a poor indicator of seizures arising from the mesial temporal region.[36]
Invasive Electroencephalogram
The use of invasive intracranial recordings using subdural grids or intracerebral depth electrodes has improved our diagnostic precision in the identification of the seizure focus. Although MTLE primarily involves the temporal lobes, the abnormal network is known to have widespread extra-temporal connectivity. It is essential to rule out other potential nodes in the network that can be independently epileptogenic. Stereo-electroencephalography (SEEG) is an important tool that registers electrical activity from very confined deep-seated brain regions that usually escape detection by usual surface recording modalities.[38] Complex signal processing techniques have been employed to understand the intrinsic properties of epileptogenic networks from electrophysiologic signals obtained from SEEG data.[39]
Unlike in scalp recording, the ictal activity recorded from intracranial electrodes detects a largely focal or regional fast beta or gamma rhythm. The focality of the rhythm on depth recording is directly proportional to the degree of hippocampal pathology.[40]
Treatment / Management
The first-line therapy for MTLE includes the initiation of appropriately chosen antiepileptic drug (AED) treatment. For patients with MTLE, the most effective AEDs are those used to treat focal epilepsies such as carbamazepine, oxcarbazepine, levetiracetam, lamotrigine, and topiramate.[41] These agents can be monotherapy or, more often, in combination to achieve adequate seizure freedom. However, it is well known that patients with MTLE often have an inadequate response to antiepileptic drug therapy.[25] Some patients who initially respond may also end up becoming medically refractory within a few years. Non-pharmacological approaches eventually play an essential role in the management of patients with medically refractory or drug-resistant MTLE. These include both surgical and neurostimulation approaches.(A1)
Surgical approaches for MTLE include open resection and other minimally invasive techniques. Standard open resective surgery is considered to be the most effective and safe treatment option for TLE with superiority to prolonged medical therapy in terms of long-term outcomes.[42] Several surgical procedures have been employed, including standard anterior temporal lobectomy, anteromedial temporal lobectomy, selective amygdalohippocampectomy, and temporal pole resection. Resective therapy has demonstrated an excellent outcome, especially if done early.[4][11] Surgical resection offers postoperative seizure freedom at two years in 60% to 80% of patients with drug-resistant MTLE, whereas longer-term follow-ups present less favorable results.[43][44] Anterior temporal lobectomy is generally safe, and the most common neurologic complication following such resective epilepsy surgery is a minor visual field deficit.(A1)
Advances in our understanding of epileptic networks have improved our ability to define the epileptogenic zone in patients with epilepsy better. The aim of disrupting epileptic networks with the smallest possible surgical lesion has led to the development of minimally invasive surgical techniques for epilepsy.[45] Minimally invasive techniques include stereotactic radiosurgery (SRS), stereotactic radiofrequency thermocoagulation (SRT), laser interstitial thermal therapy (LITT), and MRI-guided focused ultrasound ablation (FUS). SRS using gamma knife and Cyberknife deliver ionizing radiation to a focal target of mesial temporal structures in MTLE and have shown comparable postoperative seizure freedom when compared to invasive surgery.[46] Similarly, stereo-EEG (SEEG) guided thermocoagulation and laser interstitial thermal therapy (LITT) have also shown promising new developments and have been employed as alternative options to standard resective surgery.[47][48][47]
Neurostimulation for the treatment of epilepsy includes vagus nerve stimulation (VNS) responsive neurostimulation (RNS), and deep brain stimulation (DBS).[49][50][51] These are generally reserved for patients who are either not candidates for resective surgery or unwilling to undergo surgery. RNS can be used for patients with bitemporal seizure foci or foci Involving eloquent brain regions. Neurostimulation also could be an option for patients who have seizure recurrence following surgery. In patients with bitemporal epilepsy, long-term ECoG data from the RNS system can provide information enabling identification if one temporal lobe responsible for the majority of the seizures in certain patients; if so, resective surgery may be a consideration in such patients. (B3)
Apart from seizure management, patients with MTLE may have cognitive problems, psychiatric comorbidities, and psychosocial issues. A comprehensive approach to manage an individual with MTLE must take into account the cognitive and psychiatric comorbidities that often accompany this condition.[52]
Differential Diagnosis
The seizures in patients with MTLE share semiological characteristics with other types of epilepsies, such as absence seizures, insular seizures, and occipital lobe seizures. Patients with absence seizures also manifest with a blank stare and may have subtle automatisms which can mimic seizures of MTLE.[53] Patients with seizures arising from the insula can sometimes present in a very similar manner to TLE in terms of epigastric aura and oro-alimentary automatisms.[54] Some patients with occipital lobe epilepsy have seizures that rapidly spread anteriorly to the temporal lobes and can produce semiology very similar to TLE.[55]
Further, other medical conditions may mimic temporal lobe seizures such as panic attacks, tardive dyskinesia, excessive daytime sleepiness, periodic limb movement disorder, transient psychotic episodes, and psychogenic non-epileptic seizures (PNES).[56] These need to be differentiated using clinical and diagnostic tools such as video-EEG monitoring.
Enhancing Healthcare Team Outcomes
Medial temporal lobe epilepsy (MTLE) is the most common type of epilepsy that often becomes drug-resistant, requiring the need for referral to a comprehensive epilepsy center. Management of patients with pharmacoresistant MTLE is considered to be appropriate when carried out at a comprehensive level 3/4 epilepsy centers as recommended by the American Academy of Neurology (AAN) Epilepsy Quality Measurement Set.[57] These centers are equipped with diagnostic modalities, including video-EEG and multimodal neuroimaging capability, for evaluation of drug-resistant epilepsy. They employ an interprofessional team of specialists, including epileptologists, neurosurgeons, neuroradiologists, nuclear medicine specialists, clinical neuropsychologists, neuropathologists, and psychiatrists who can address all the different aspects of care that are needed to be provided to these patients. After performing a comprehensive evaluation, the team meets at a conference to pool all the available information about the patient and come up with an appropriate management plan. Some patients who are thought to have drug-resistant epilepsy may not have epilepsy. For others who are determined to have focal onset epilepsy, the potential surgical candidates are identified.[58]
Epilepsy centers are still underutilized, resulting in suboptimal management of patients with drug-resistant epilepsy, including MTLE. Any patient with epilepsy who have failed a trial of two antiepileptic medication (appropriately chosen for the seizure type/epilepsy syndrome) is considered to have drug-resistant epilepsy and should receive a referral to a comprehensive epilepsy center.[59] Early referral to a comprehensive epilepsy center can provide the patient with the best opportunity for optimal seizure control and potential seizure freedom. It can also prevent psychosocial trauma, reduce the number of disability-associated life years, improve quality of life, and decrease the risk of sudden unexpected death in epilepsy patients (SUDEP).[60]
Neuroscience nurses are often involved in the care of these patients, providing monitoring, family and patient education, and facilitating evaluation and communication. Pharmacists counsel patients and families about the importance of compliance and potential side effects, verify dosing/titration and consult with the prescriber regarding agent selection. These examples of interprofessional interaction can lead to improved patient outcomes. [Level 5]
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