Hippocampal sclerosis

Hippocampal sclerosis also commonly referred to as mesial temporal sclerosis, is the most common brain pathological lesion underyling intractable temporal lobe epilepsy ¹. Hippocampal sclerosis is the commonest cause of drug-resistant epilepsy in adults, and is associated with alterations to structures and networks beyond the hippocampus ². In a European series of 9523 patients with epilepsy undergoing surgery, hippocampal sclerosis was identified in 36.4%, long-term epilepsy-associated tumors in 23.6%, and focal cortical dysplasias in 19.8% ³. It is not known whether hippocampal sclerosis exists before the onset of epilepsy or whether it is caused by seizures ⁴. Its has been proposed that childhood seizures cause hippocampal sclerosis. Hippocampal sclerosis is seen in up to 65% of autopsy studies, although significantly less on imaging.

Hippocampal sclerosis is now recognized as one of the main causes of focal epilepsy and is present in approximately 10% of adults with new-onset focal epilepsy ⁵. Moreover, hippocampal sclerosis often causes refractory epilepsy and is the sole pathology in about a third of all surgical resections for epilepsy and is an associated pathology so-called dual pathology in approximately 5% ⁶. However, the hippocampus has a twofold interest in epilepsy, in addition to being a cause of epilepsy, the hippocampus is vulnerable to damage from seizure activity ². In particular, prolonged seizures (status epilepticus) can result in hippocampal sclerosis ². The hippocampus is also vulnerable to other insults including traumatic brain injury, and inflammation. Hippocampal sclerosis can occur in association with other brain lesions; the prevailing view is that it is probably a secondary consequence. In such instances, successful surgical treatment usually involves the resection of both the lesion and the involved hippocampus ². This dichotomous role of hippocampal damage as the cause and result of seizures stems possibly from its physiological role in memory formation and neuronal plasticity ⁷.

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 (see Figure 2) ⁸. Neuronal cell loss is associated with reactive astrogliosis causing tissue stiffening, which has been traditionally termed as “Ammon’s horn sclerosis” ⁹. 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 ¹⁰. Abnormalities have also been noted in the dentate gyrus in the form of granule cell dispersion ¹¹. Additionally, variable cell loss is also detectable in adjacent cortical regions, including subiculum, entorhinal cortex, and amygdala.

Experimental data have pointed to numerous neuroprotective strategies to prevent hippocampal sclerosis. Initial neuroprotective strategies aimed at glutamate receptors may be effective, but later, metabolic pathways, apoptosis, reactive oxygen species, and inflammation are involved, perhaps necessitating the use of interventions aimed at multiple targets ². Some of the therapies that are used to treat status epilepticus may be neuroprotective. However, prevention of neuronal death does not necessarily prevent the later development of epilepsy or cognitive deficits. Perhaps, the most important intervention is the early, aggressive treatment of seizure activity, and the prevention of prolonged seizures.

Figure 1. Hippocampal sclerosis

Footnote: Adult with epilepsy on medication. Moderate degree of volume loss of the left temporal lobe (temporal lobe atrophy) very much excessive for the patient’s age including extensive sclerosis of the hippocampus consistent with a structural cause for epilepsy. The left temporal horn is dilated measuring 8 mm vis-à-vis 2 mm for the normal contralateral side. Marked volume loss of the left hippocampus. The remainder of the brain is normal in appearance.

Figure 2. Hippocampal sclerosis

Footnote: Hippocampal atrophy ipsilateral to the seizure focus. The patient has increased glucose metabolism in the right hippocampus without a similar increase in CMRO2 (oxidative metabolism positron emission tomography [PET]). The hyperintensity on the fluid-attenuated inversion recovery (FLAIR) sequence was due to acute seizure activity and not traumatic hemorrhage. Magnetic resonance imaging scan of brain at 6 months shows right hippocampal atrophy and also right temporal lobe atrophy.

Abbreviations: CMRO2 = oxidative metabolism positron emission tomography (PET); FDG = fluorodeoxyglucose PET; PIH = postinjury hour.

[Source ¹² ]

Figure 3. Hippocampal sclerosis histopathology

Footnote: Histopathologic subtypes of hippocampal sclerosis. (A) International League Against Epilepsy (ILAE) hippocampal sclerosis type 1 shows pronounced preferential pyramidal cell loss in both CA4 and CA1 sectors. Damage to sectors CA3 and CA2 is more variable but frequently visible. (B) ILAE hippocampal sclerosis type 2 (CA1 predominant neuronal cell loss and gliosis): This is a rarer and atypical hippocampal sclerosis pattern characterized by neuronal loss primarily involving CA1 compared with other subfields where damage is often not detectable by visual inspection (C) ILAE hippocampal sclerosis type 3 (CA4 predominant neuronal cell loss and gliosis): This is characterized by restricted cell loss mostly in CA4. (D) No hippocampal sclerosis, gliosis only. All stainings represent NeuN immunohistochemistry with hematoxylin counterstaining using 4-μm-thin paraffin embedded sections. DGe/DGI, external/internal limbs of dentate gyrus; Sub, subiculum. Scale bar in A = 1,000 μm (applies also to B–D).

[Source ¹³ ]

Hippocampal sclerosis classification

Several classification systems have been proposed for hippocampal sclerosis. The most widely used is the new International League Against Epilepsy (ILAE) classification system (see Table 1), which divides hippocampal sclerosis into three types based on a semi-quantitative survey of segmental cell loss within hippocampal subfields. International League Against Epilepsy (ILAE) hippocampal sclerosis as type 1, previously termed classical hippocampal sclerosis, occurring in 60 to 80% of resections has both CA1 and CA4 loss; ILAE Type 2 has predominant CA1 sclerosis, occurring in 5 to 10% and ILAE Type 3 also termed end-folium sclerosis mainly involving CA4 and dentate gyrus, occurring in 4 to 7% and gliosis without hippocampal sclerosis, which may be seen in up to 20% of temporal lobe resections ¹⁴.

The International League Against Epilepsy (ILAE) classification is important because it may relate to surgical outcome–with the no hippocampal sclerosis but gliosis and the type 2 hippocampal sclerosis having the poorest outcomes (∼40% completely seizure free with 2-year follow-up) compared with approximately 70% seizure free with type 1 hippocampal sclerosis ¹⁵.

The other important question is whether the pattern of damage relates to the nature of the precipitating event, age at the time of the precipitating event, and duration of epilepsy and seizure frequency. Interestingly, seizure frequency and duration of epilepsy had minimal impact on the type of hippocampal sclerosis. However, events before the age of 3 years tended to be associated with type 1. Type 3 hippocampal sclerosis and no hippocampal sclerosis were less strongly associated with the occurrence of identifiable preceding events, which tended to happen later, during adolescence ¹⁴.

From a clinical perspective, it would be ideal to identify the pattern of cell loss before resection. Although magnetic resonance imaging (MRI) studies can reliably determine the severity of hippocampal sclerosis (confirmed by histopathology) ¹⁶, automated programs with conventional clinical MRI (1.5 T or 3 T) cannot yet reliably differentiate changes in specific hippocampal subfields ¹⁷. The severity of hippocampal sclerosis does not, however, directly translate to surgical success, but may impact the clinical pattern of the seizures, with more severe hippocampal sclerosis being associated with symptoms and signs that are usually ascribed to extratemporal lobe epilepsies ¹⁸. The challenge of identifying specific patterns of cell loss may be surmounted by increasingly sophisticated acquisition protocols at higher field strengths.

Neuronal loss and gliosis may extend beyond the hippocampus and affect the amygdala, parahippocampal gyrus, and entorhinal cortex ¹⁹. Entorhinal cortex neuronal loss has also been described in the absence of hippocampal sclerosis ²⁰. This, and the observation that the entorhinal cortex can alone maintain seizure-like activity ²¹, suggests that there may an important role for this region in the generation of mesial temporal seizures.

Hippocampal sclerosis is also associated with brain abnormalities further afield, with neuronal loss reported in the thalamus ²². Indeed, thalamic atrophy seems a common finding ²³, indicating that there are more widespread structural changes associated with hippocampal sclerosis, supporting the concept of medial temporal lobe epilepsy as a network phenomenon involving disparate brain areas ²⁴. It is unclear whether the more widespread structural and functional abnormalities associated with hippocampal sclerosis are part of the syndrome or the result of secondary involvement of these regions due to repeated seizures generated from medial temporal structures. However, more widespread structural abnormalities detected by MRI do seem to predict poorer surgical outcomes ²⁵.

Table 1. International League Against Epilepsy classification of hippocampal sclerosis

Type 1	CA1: > 80% cell loss CA2: 30–50% cell loss CA3, 30–90% cell loss CA4 40–90% cell loss Dentate gyrus 50–60% granule cell loss
Type 2	Predominant neuronal loss in CA1, affecting almost 80% of pyramidal cells. All other sectors show mild cell loss barely visible by qualitative microscopic inspection.
Type 3	Predominant cell loss in CA4 (∼50% cell loss) and the dentate gyrus (35% cell loss), whereas CA3 (< 30%), CA2 (< 25%), and CA1 (< 20%) are only moderately affected
Type 4	No hippocampal sclerosis and gliosis

[Source ¹³ ]

Hippocampal sclerosis causes

Hippocampal sclerosis can have more than one cause, and often the cause is a complex interplay between genetic background and environmental insults. Controversy exists as to the causative mechanism: is hippocampal sclerosis a result of temporal lobe epilepsy or vice versa? In children with newly diagnosed epilepsy, only ~ 1% have evidence of hippocampal sclerosis on imaging ²⁶. Furthermore, in adults 3-10% of cases of hippocampal sclerosis demonstrate bilateral changes even though symptoms may be unilateral ¹.

In the same year that Sommer was proposing hippocampal sclerosis to be the cause of epilepsy, Pfleger ²⁷ published evidence that the hippocampus is particularly vulnerable to damage by seizures. Pfleger ²⁷ described hemorrhagic lesions in the mesial temporal lobe of a patient dying in status epilepticus, and concluded that neuronal necrosis was the result of impaired blood flow or metabolic disturbances that occurred during the seizures. More recent postmortem studies have also shown significant acute neuronal loss in the hippocampus of patients dying in convulsive status epilepticus ²⁸. DeGiorgio et al ²⁸ compared the hippocampi from five patients dying in status epilepticus, five patients with epilepsy who had a similar degree of physiological compromise (e.g., hypoglycemia, hypotension and hypoxia), and five controls. The neuronal densities were least in those dying with status epilepticus. Interestingly, a later unselected postmortem series identified that there are patients who have had a long history of seizures and even episodes of status epilepticus with no evidence of damage in the hippocampus, suggesting that status epilepticus alone may not be sufficient to cause neuronal damage ²⁹.

From the other perspective, a significant cerebral insult or initial precipitating injury occurring early in life, such as a febrile or prolonged seizure, is often reported (between 30–50% of cases, but up to 80% in one surgical series) in retrospective studies of patients with hippocampal sclerosis ³⁰. The “injury” hypothesis implies that this insult irreversibly damages or alters the hippocampus resulting in a template for the progression to hippocampal sclerosis following a “latent” interval. There appears to be an age-specific sensitivity for this injury, with more severe neuronal loss found when the initial precipitating injury occurs before ages of 4 to 7 years ³¹. The most direct evidence of the association is the observation with serial neuroimaging that hippocampal sclerosis may follow prolonged febrile convulsions ³². Approximately 10% of children with febrile seizures lasting > 30 minutes (febrile status epilepticus) have an associated high T2-weighted signal in the hippocampus with later evolution to hippocampal sclerosis in most ³³. In the other 90%, there was evidence of decreased hippocampal growth, suggesting subtle hippocampal injury ³³. Whether there were subtle abnormalities of the hippocampus that may have predisposed to hippocampal sclerosis was unclear. Importantly, in children, the development of hippocampal damage does not seem to be restricted to those who have had febrile status epilepticus, but can occur following any cause of convulsive status epilepticus ³⁴.

Head injury can also result in hippocampal sclerosis. In rat models, fluid percussion injury to the dura results in interneuron loss in the hippocampus ³⁵. The mechanism by which this occurs is unknown. The neuronal loss is accompanied by enhanced excitability of the hippocampus, and eventually spontaneous seizures. Notably, the interneuronal loss is progressive, occurring months after the insult ³⁶. An interesting observation in humans is that traumatic brain injury may be associated with covert status epilepticus that then results in hippocampal injury ³⁷. These experimental and human studies raise a fundamental question: Why is it that only a minority develops hippocampal sclerosis following identical brain insults?

Temporal lobe epilepsy is generally regarded as an acquired disorder with only a small genetic contribution. However, there may be common genetic variants that predispose to hippocampal sclerosis. Recently, such polymorphisms in a region of the genome encoding sodium channel subunits, in particular SCN1A, have been associated with the occurrence of febrile seizures and hippocampal sclerosis ³⁸. This indicates that the risk of hippocampal sclerosis following a brain insult also depends upon the person’s genetic background.

In addition, an underlying maldevelopment of the hippocampus could predispose to hippocampal sclerosis and also to febrile seizures ³⁹; this may partly explain why hippocampal sclerosis is often unilateral. In an MRI study of families with familial febrile convulsions, there were subtle pre-existing hippocampal abnormalities ⁴⁰ and hippocampal sclerosis has also been reported in patients in association with isolated malformations of the hippocampus ⁴¹. In addition, persistence of calretinin positive Cajal–Retzius cells may be found in the sclerosed hippocampus, particularly when associated with febrile seizures ³⁹. These cells secrete reelin, which plays a critical role in neuronal organization in the developing brain; it is possible that their persistence is due to either a developmental abnormality or an “insult” that predated the febrile seizures. A further argument supporting a developmental basis for hippocampal sclerosis comes from the observation that hippocampal sclerosis is often observed in association with subtle cytoarchitectural malformations in the neocortex, such as microdysgenesis ⁴². There may, therefore, be a more widespread maldevelopmental process involving both mesial and lateral temporal lobe structures.

Hippocampal sclerosis is also well recognized to occur in association with more severe cortical malformations, vascular malformations, and low-grade glioneuronal tumors ⁴³. Here, the hypothesis is that the extrahippocampal lesion generates seizures or subclinical seizure activity that results in neuronal loss in the hippocampus. In such patients (i.e., those with dual pathology), removing both the lesion and the abnormal hippocampus has the best outcome in terms of seizure control, emphasizing the role of the hippocampus in temporal lobe seizures even when there is a second pathology ⁴³.

Hippocampal sclerosis may be progressive in some patients ⁴⁴, suggesting a paradigm in which an epileptogenic hippocampus generates seizures that then cause further damage to the hippocampus and more widespread structures, including the contralateral hippocampus. In support of this hypothesis, early surgical treatment (when the disease is more “confined”) results in better outcomes than late surgical intervention ⁴⁵.

Lastly, infections can cause the hippocampal sclerosis. There is evidence that it can be associated with neurocysticercosis, although this is likely to be dual pathology rather than a direct impact on the hippocampus ⁴⁶. Viral encephalitis often targets mesial temporal structures with the evolution to bilateral hippocampal sclerosis and profound memory difficulties emphasizing the importance of aggressive early treatment; hippocampal resection of those with an encephalitic etiology can still render people seizure free ⁴⁷. Infection with herpes virus may also frequently underlie the occurrence of febrile seizures and later hippocampal sclerosis ⁴⁸. More recently, autoimmune causes of hippocampal sclerosis have been identified, such as voltage-gated potassium channel antibodies ⁴⁹. Usually, these autoantibodies result in an acute or subacute encephalitis with enlargement, increased T2-weighted signal, and restricted diffusion of the mesial temporal lobe structures evident on MRI. Later, hippocampal sclerosis can occur, which may be unilateral or bilateral, again emphasizing the importance of aggressive early treatment ⁵⁰. In some people with established hippocampal sclerosis, autoantibodies can be found, but it is unclear whether they are pathogenic or an epiphenomenon.

Hippocampal sclerosis prevention

Endogenous neuroprotection

There are several endogenous neuroprotection pathways that could be targeted in neuroprotection. One important observation is that preconditioning (i.e., brief seizures protecting against longer seizures) seems to occur in epilepsy in a similar manner to that described in stroke. Such epileptic preconditioning alters gene expression in processes involved with calcium signaling, ion channels, and excitatory neurotransmitter receptors ⁵¹. These experimental observations suggest that the impact of status epilepticus may be less severe in people with pre-existing epilepsy.

What about specific pathways involved in neuroprotection? A variety of signaling pathways are involved in neuronal death and endogenous neuroprotection. Among these are the phosphoinositide 3-kinase (PI3-kinase)/Akt and the extracellular signal regulated kinase 1/2 (ERK1/2) pathways that can be activated through several different routes including neurotrophins and calcium entry through NMDA receptors. The PI3 kinase/Akt pathway is intimately related to the mTOR pathway, inhibitors of which are being investigated for antiepileptogenic potential ⁵². Phosphorylated (activated) Akt inactivates several proapoptotic proteins such as Bad, caspase-9, and transcription factors of the forkhead family ⁵³. Thus, NMDA receptor activity can be neuroprotective. Indeed, NMDA receptor activation has a dichotomous role in neuronal survival/death; low level, chronic activation of synaptic NMDA receptors is neuroprotective, whereas sudden and excessive activation of extrasynaptic NMDA receptors is neurotoxic ⁵⁴.

Reactive oxygen species can also play an important role in neuronal death. During seizure activity, these are also produced through the excessive activation of NMDA receptors and are mainly generated by cytosolic enzymes (such as NADPH oxidase) ⁵⁵. There are, however, endogenous mechanisms to protect against these: These endogenous mechanisms are boosted by the transcription factor, nuclear factor erythroid 2-related factor 2 (Nrf2). Nrf2 binds to the cis-acting antioxidant response elements in the nucleus, a specific promoter sequence for genes encoding phase II and antioxidant cytoprotective proteins, including glutathione S-transferase and NADPH:quinone oxidoreductase ⁵⁶. There is evidence that the ketogenic diet upregulates Nrf2 and may mediate a neuroprotective effect through this mechanism ⁵⁷. However, reactive oxygen species also show a dichotomous role. Peroxynitrite, which is a potent reactive oxygen species that can result in neuronal death, at very low concentrations activates the Akt pathway and thus may be neuroprotective ⁵⁸. ERK1/2 can be activated by a variety of extracellular stimuli including neurotrophins ⁵⁹. ERK1/2 activation may initially counter oxidative stress, but when cellular defenses are exhausted, it serves as a signal to trigger cell death ⁶⁰.

Together, many of these studies indicate that the binary view of many of these enzymes, receptors, and pathways as neurotoxic or neuroprotective is far too simplistic, and there is often a form of dualism with pathways having both neuroprotective and neurotoxic potential.

Exogenous neuroprotection

Undoubtedly, the most effective way to prevent seizure-related damage is to halt seizure activity. Indeed, the treatment of status epilepticus in the premonitory phases before status epilepticus has become established may prevent many of the pathological consequences ⁶¹. Therefore, early recognition and administration of effective treatment are paramount. If seizures continue, then the excitotoxic cascade is activated. The NMDA receptor and metabotropic glutamate group I receptor activation result in both calcium influx into the neuron and also release of calcium from internal stores ⁶². Other receptors and ion channels, such as voltage-gated calcium channels and calcium-permeable AMPA receptors, may also contribute to intracellular calcium accumulation. In addition, seizure-induced ion shifts may cause neuronal swelling and necrotic cell death. Inhibition of NMDA receptors before or soon after status epilepticus gives substantial and widespread neuroprotection ⁶³, but it is likely that NMDA receptor antagonists will need to be given early to prevent calcium accumulation.

Calcium accumulation activates many distinct and interconnected downstream mechanisms, including the extrinsic caspase pathway through caspase 8 activation, the intrinsic caspase pathway activated by cytochrome c release from mitochondria, BCL-2 pathways, the formation of reactive oxygen species such as peroxynitrite, disruption of mitochondrial function through mitochondrial calcium accumulation, activation of calpain 1, activation of poly(ADP-ribose) polymerase-1, and so forth ⁶⁴. There is considerable controversy about the relative roles of these different pathways. This whole area is further confounded by the possibility that different pathways are activated in different seizure models at different times, and that the mechanism of neuronal death may be region/cell specific ⁶⁵. There are, however, simple measures that could be used to neuroprotect, such as anaplerosis, the replenishment of Krebs’ cycle substrates ⁶⁶. The ketogenic diet could contribute to neuroprotection through this mechanism.

Independent from neuronal calcium accumulation, inflammatory mechanisms have also been implicated in neuronal death and dysfunction during prolonged seizures, and interventions targeted at brain inflammation in experimental model have shown some success ⁶⁷.

Clinically, an important question is whether antiepileptic (antiseizure) drugs have any neuroprotective roles beyond their antiseizure effect. There is reasonable preclinical evidence that many of our present antiepileptic drugs have potential neuroprotective properties, but the mechanisms underlying this are not fully elucidated ⁶⁸. Furthermore, many of the preclinical studies are confounded by an effect of drugs on seizure severity, making it difficult to dissociate the antiseizure from the neuroprotective effect.

Hippocampal sclerosis symptoms

Most patients with hippocampal sclerosis present with complex partial temporal lobe epilepsy.

Common features of temporal lobe epilepsy include the following:

• Memory impairment
• Aura (now called focal aware)

Auras/focal aware may be classified by symptom type, as follows:

• Sensory – auditory, gustatory, hot-cold sensations, olfactory, somatosensory, vestibular, visual
• Autonomic – Heart rate change (asytole, bradycardia, palpitations, tachycardia), flushing, gastrorintestinal, pallor, piloerection, respiratory
• Cognitive/psychic – Déjà vu or jamais vu, dissociation, depersonalization or derealization, forced thinking, aphasia/dysphasia, memory
• Emotional/affective – agitation, aggression, anger, anxiety, fear, paranoia, pleasure, crying (dacrystic) or laughing

Examples of auras include:

• A sudden sense of unprovoked fear or joy
• A deja vu experience — a feeling that what’s happening has happened before
• A sudden or strange odor or taste
• A rising sensation in the abdomen, similar to being on a roller coaster

Sometimes temporal lobe seizures impair your ability to respond to others. This type of temporal lobe seizure usually lasts 30 seconds to two minutes. Characteristic signs and symptoms include:

• Loss of awareness of surroundings
• Staring
• Lip smacking
• Repeated swallowing or chewing
• Unusual finger movements, such as picking motions

Features of temporal lobe complex partial seizure may include the following:

• Aura/focal ware
• Motionless stare, dilated pupils, and behavioral arrest
• Automatism – Oral-facial, eye blinking, alimentary, manual or unilateral dystonic limb posturing, perserveration, vocalization/speech
• Possible evolution to a secondarily generalized tonic-clonic seizure, now called bilateral tonic clonic
• Postictal period that can include confusion, aphasia, or (by definition) amnesia

After a temporal lobe seizure, you may have:

• A period of confusion and difficulty speaking
• Inability to recall what occurred during the seizure
• Unawareness of having had a seizure
• Extreme sleepiness

In extreme cases, what starts as a temporal lobe seizure evolves into a generalized tonic-clonic (grand mal) seizure — featuring convulsions and loss of consciousness.

Hippocampal sclerosis diagnosis

After a seizure, your doctor will thoroughly review your symptoms and medical history. Your doctor may order several tests to determine the cause of your seizure and evaluate how likely it is that you’ll have another one.

Tests may include:

• Neurological exam. Your doctor may test your behavior, motor abilities and mental function to determine if you have a problem with your brain and nervous system.
• Blood tests. Your doctor may take a blood sample to check for signs of infections, genetic conditions, blood sugar levels or electrolyte imbalances.
• Electroencephalogram (EEG). Electrodes attached to your scalp record the electrical activity of your brain, which shows up as wavy lines on an EEG recording. The EEG may reveal a pattern that tells doctors whether a seizure is likely to occur again, or help rule out other conditions that mimic epilepsy.
• Computerized tomography (CT) scan. A CT scan uses X-rays to obtain cross-sectional images of your brain. CT scans can reveal abnormalities in your brain that might cause a seizure, such as tumors, bleeding and cysts.
• Magnetic resonance imaging (MRI). An MRI uses powerful magnets and radio waves to create a detailed view of your brain. Your doctor may be able to detect lesions or abnormalities in your brain that could lead to seizures.
• Positron emission tomography (PET). PET scans use a small amount of low-dose radioactive material that’s injected into a vein to help visualize active areas of the brain and detect abnormalities.
• Single-photon emission computerized tomography (SPECT). A SPECT test uses a small amount of low-dose radioactive material that’s injected into a vein to create a detailed, 3-D map of the blood flow activity in your brain that happens during a seizure. Doctors may also conduct a form of a SPECT test called subtraction ictal SPECT coregistered to magnetic resonance imaging (SISCOM), which may provide even more-detailed results.

Magnetic resonance imaging (MRI)

MRI is the modality of choice to evaluate the hippocampus, however dedicated temporal lobe epilepsy protocol needs to be performed if good sensitivity and specificity is to be achieved ¹. Thin section angled coronal sequences at right angles to the longitudinal axis of the hippocampus are required, to minimize volume averaging.

Coronal volume and coronal high resolution T2WI/FLAIR are best to diagnose hippocampal sclerosis.

Findings include ⁶⁹:

• reduced hippocampal volume: hippocampal atrophy
• increased T2 signal
• abnormal morphology: loss of internal architecture (interdigitations of hippocampus), stratum radiata, a thin layer of white matter separates the dentate nucleus and Ammon horn

Although comparing left to right side is easiest, it must be remembered that up to 10% of cases are bilateral, and thus if symmetry is the only feature being evaluated, many cases may be misinterpreted as normal.

Often mentioned, but probably one of the least specific findings, is enlargement of the temporal horn of the lateral ventricle ¹. If anything, care must be taken not to allow an enlarged horn to trick you into thinking the hippocampus is reduced in size.

When severe and long standing, additional associated findings include ⁶⁹:

• atrophy of the ipsilateral fornix and mammillary body
• increased signal and or atrophy of the anterior thalamic nucleus
• atrophy of the cingulate gyrus
• increased signal and/or reduction in the volume of the amygdala
• reduction in the volume of the subiculum
• dilatation of temporal horn and temporal lobe atrophy
• collateral white matter and entorhinal cortex atrophy
• thalamic and caudate atrophy
• ipsilateral cerebral hypertrophy
• contralateral cerebellar hemiatrophy
• loss of grey-white matter interface in the anterior temporal lobe ¹
• reduced white matter volume in the parahippocampal gyrus ¹

Additional 3D volumetric studies can be performed, and although time consuming to post-process may be more sensitive to subtle hippocampal volume loss. Gadolinium is not required ¹.

T2 relaxometry may also be useful in detecting cases of hippocampal sclerosis ¹.

Diffusion MRI

As a result of neuronal loss, the extracellular space is enlarged and thus diffusion of water molecules is greater on the affected side, resulting in increased values on the affected side (higher signal on ADC).

Conversely, due to neuronal dysfunction and swelling, diffusion is restricted following a seizure, and thus values are lower ¹.

MR spectroscopy

MR spectroscopy findings typically represent neuronal dysfunction ¹:

• decreased NAA and decreased NAA/Cho and NAA/Cr ratios
• decreased MI in ipsilateral temporal lobe
• increased lipid and lactate soon after as seizure

MR perfusion

MR perfusion demonstrates similar changes to SPECT with blood perfusion depending on when the scan is obtained.

During the peri-ictal phases, perfusion is increased, not only in the mesial temporal lobe but often in large parts of temporal lobe and hemisphere. In interictal periods, conversely, perfusion is reduced ¹.

Nuclear medicine

SPECT (Tc-99m HMPAO or ECD) and PET (F18-FDG) imaging are also a useful adjuncts, with both ictal and interictal scans demonstrating abnormalities ⁷⁰:

• ictal scan: hyperperfusion
• interictal scan: hypoperfusion

Other causes of temporal lobe epilepsy should be considered, especially as small temporal lobe cortical tumors can have similar appearances.

Hippocampal sclerosis treatment

Temporal lobe epilepsy is initially managed medically with anti-epileptic agents. In patients who are refractory to medical management temporal lobectomy or selective amygdalohippocampectomy may be performed. Anterior temporal lobectomy is successful in 75-90% of patients with hippocampal sclerosis.

Following a diet that’s high in fat and low in carbohydrates, known as a ketogenic diet, can improve seizure control. Variations on a high-fat, low-carbohydrate diet, such as the low glycemic index and modified Atkins diets, may be less effective. However, they aren’t as restrictive as the ketogenic diet and might provide some benefit.

Medications

Many medications are available to treat temporal lobe seizures. However, many people don’t achieve seizure control with medications alone, and side effects, including fatigue, weight gain and dizziness, are common.

Older antiepileptic drugs used for seizure control in temporal lobe epilepsy have some long-term side effects and require lab monitoring:

• Phenytoin
• Carbamazepine
• Valproate
• Phenobarbital

Newer antiepileptic drugs appear to be comparably effective but with fewer side effects and don’t requre lab monitoring for the most part:

• Gabapentin
• Pregabalin
• Topiramate
• Lamotrigine
• Levetiracetam
• Oxcarbazepine
• Zonisamide
• Lacosamide
• Briviacetam
• Clobazam
• Rufinamide
• Perampanel
• Vigabatrin (for intractable)
• Felbamate (for intractable)

Discuss possible side effects with your doctor when deciding about treatment options. Also ask what effect your seizure medications and other medications you take, such as oral contraceptives, may have on each other.

Surgical or other procedures

When anti-seizure medications aren’t effective, other treatments may be an option:

• Surgery. The goal of surgery is to stop seizures from happening. This is often done through a traditional surgery, where surgeons operate to remove the area of the brain where seizures begin. In certain people, surgeons may be able to use MRI-guided laser therapy as a less invasive way to destroy the area of damaged tissue that causes seizures. Surgery works best for people who have seizures that always originate in the same place in their brains. Surgery generally isn’t an option if your seizures come from more than one area of the brain, your seizure focus can’t be identified or your seizures come from a region of the brain that performs vital functions.
  • Temporal lobectomy is the definitive treatment for medically intractable temporal lobe epilepsy with high seizure-free rate.
• Vagus nerve stimulation (VNS). A device implanted underneath the skin of your chest stimulates the vagus nerve in your neck, sending signals to your brain that inhibit seizures. With vagus nerve stimulation, you may still need to take medication, but you may be able to lower the dose.
• Responsive neurostimulation. During responsive neurostimulation, a device implanted on the surface of your brain or within brain tissue can detect seizure activity and deliver an electrical stimulation to the detected area to stop the seizure.
• Deep brain stimulation (DBS) is awating FDA approval but is available in other countries.

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