16 Mesial Temporal Sclerosis in Children
Temporal lobe epilepsy (TLE) is the most common partial seizure disorder in the adult population, and the most frequent cause is mesial temporal sclerosis (MTS). Seizures usually begin in late childhood or early adolescence. The prevalence of MTS among children with newly diagnosed seizure disorders is reportedly much lower: approximately 1% of those presenting with initial recurrent seizures and even lower when evaluating children younger than 12 years.1–3 Ng et al recently studied the baseline prevalence of childhood MTS.4 Their review of 3100 brain magnetic resonance imaging (MRI) reports from children younger than 14 years old (obtained for a variety of reasons, including seizure, head injury, brain tumor, headache, and developmental delays) showed that 24 (0.77%) had MTS. All patients with MTS in this series initially presented with seizures, so the authors concluded that although MTS is uncommon in children, it is invariably presents with seizures.
Pathophysiology
The mesial temporal structures include the hippocampus, amygdala, and parahippocampal gyrus. MTS refers to atrophy and gliosis of the hippocampus. Synonyms for MTS include Ammon’s horn sclerosis and hippocampal sclerosis. MTS is the cause for TLE in 50 to 65% of patients undergoing temporal lobectomy.5,6 Pathological variants observed in MTS include hippocampal neuronal loss and gliosis, neuronogenesis, and axonal reorganization.7 Classic Ammon’s horn sclerosis is defined as primary neuronal loss involving sectors CA1 and CA4 (the sectors most vulnerable to hypoxic damage), occurring less frequently in sectors CA2 and CA3.8 Total Ammon horn sclerosis consists of severe neuronal loss involving all four sectors.
The molecular pathology of MTS is not completely understood. Certain types of medically refractory epilepsy may be the result of excitotoxicity secondary to excessive glutamatergic activity. Elevated extracellular glutamate levels, glutamate receptor upregulation, and loss of glutamine synthetase (a glutamate-metabolizing enzyme) have been demonstrated in affected brain tissue of patients with MTS.9 This observation has been referred to as the “glutamate hypothesis” of MTS pathogenesis. Astrocytes, with their important role in glutamate reuptake and metabolism, probably play an important role in this process, because excessive astrocyte proliferation and accumulation and release of astrocytic glutamate has been demonstrated in MTS.9,10
Etiologies
There is a great deal of controversy regarding the causality between MTS and TLE (i.e., whether MTS is the cause or the result of TLE). Prolonged febrile seizures, head injury, nonfebrile status epilepticus, encephalitis, hypertensive encephalopathy, and viruses have been implicated as potential underlying causes for MTS in children.11–14 MTS can also be a late complication of posttransplant cyclosporine-A neurotoxicity (including in children).15,16 Dual pathology [i.e., the presence of other lesions, such as malformations of cortical development (MCD) in sites outside the hippocampus or even the temporal lobe] has been observed in approximately one third of patients who have undergone temporal lobectomy as treatment for intractable seizures.17–22 MTS can be bilateral in up to 20% of patients.6
MTS and Febrile Seizures
The link between MTS and severe febrile convulsions (FCs) was suggested by Falconer et al.23 MRI studies have suggested a causal link between prolonged and focal FCs in some patients, although some infants in that series also had evidence of pre-existing abnormalities (this has not been consistent between series).24,25 Up to 30% of TLE patients with MTS in surgical series have a history of prolonged FCs and status epilepticus. 26 Up to 3.5% of patients with a history of febrile seizures later develop epilepsy.27,28 Three potential hypotheses exist to explain the association with MTS and FCs (explained in ref. 29). One is that FCs cause MTS through acute hippocampal injury, which then later results in the emergence of TLE. The second hypothesis is that FCs and MTS are both a consequence of another abnormality that ultimately results in TLE. Finally, MTS may precede FCs. Other investigators believe there is no actual association between FCs and MTS. Patients with a history of complex (not simple) febrile seizures (defined in the National Collaborative Perinatal Project as those lasting greater than 15 minutes, with evidence of focal convulsions, or more than two seizures in a 24-hour period27) have an increased incidence of epilepsy and MTS.22–31 The incidence of MTS after complex febrile seizures is related directly to the number of complex features.31 However, more recent studies with long-term follow-up have questioned the strength of this association. Tarkka et al followed 24 patients with prolonged febrile seizures, 8 with an unprovoked seizure after the first event and 32 control subjects with a single simple febrile seizure over a mean of 12.3 years and found that none fit MRI criteria for MTS at the time of follow-up.32
Human Herpes Virus 6
Human herpes virus 6 (HHV-6) is a ubiquitous β-herpesvirus associated with roseola infantum. HHV6 has been shown to cause limbic encephalitis in immunocompromised hosts and is thought to cause seizures, meningitis, and multiple sclerosis in otherwise healthy individuals.13,14 Theodore et al examined TLE specimens and discovered that hippocampal astrocytes contained active HHV6B in approximately two thirds of MTS patients.14 They proposed that HHV6B may cause excitotoxicity by inhibiting transport of excitatory amino acids within astrocytes and by causing neuronal damage. A great deal of evidence also links HHV6 to febrile seizures, indicating a potential link between MTS and FC.
Dual Pathology
Postsurgical pathological evaluation of temporal lobectomy specimens in patients with MTS has often revealed not only hippocampal sclerosis, but also coexistent MCD. Mohamed et al reported mild-to-moderate MCD in 79% of specimens received from 34 children and adolescents who underwent anteromesial temporal resection.33 Although the interictal electroencephalogram (EEG) in these patients was not as localizing as in patients with MTS alone, the finding of dual pathology did not predict a poorer postsurgical outcome. These findings are in contrast to a more recent evaluation by Kan et al showing that of 19 patients identified with MTS, only 3 had dual pathology (16%) and of those, only one third were seizure free after surgical resection.34
Presentation
Older children and adolescents with MTS often present initially with complex partial seizures that frequently secondarily generalize. The seizures can be triggered by psychological or physical stress, sleep deprivation, or hormonal fluctuations in adolescent girls. They may be preceded by a combination of auras such as a rising gastric sensation, déjà vu, psychic auras (e.g., fear, anxiety, or other strong emotions), olfactory auras, or autonomic changes (e.g., tachycardia, pallor, mydriasis). The ictal event typically lasts 1 to 2 minutes and consists clinically of staring and automatisms such as lip smacking, puckering, chewing, or swallowing, hand picking, rubbing, or fumbling. Importantly, hand automatisms are seen more frequently ipsilateral to the MTS with contralateral dystonic posturing.35 Patients can behave in a semipurposeful manner during these episodes but do not retain full awareness of the event. The postictal period may be of variable duration and may last up to several hours.36 However, as in most of pediatric neurology, signs can be age dependent. Signs and symptoms are more difficult to assess when evaluating infants and toddlers with suspected MTS because assessment of subjective aura and impairment of consciousness is challenging in this age group. Bourgeois et al described the distinctive features of complex partial seizures in infants as follows: “(1) a predominance of behavioral arrest with possible impairment of consciousness, (2) no identifiable aura, (3) automatisms that are discrete and mostly orofacial, (4) more prominent convulsive activity, and (5) a longer duration (>1 minute).”1 Brockhaus and Elger studied 29 children with TLE and found that symmetrical limb motor signs, posturing (as expected in frontal lobe seizures), and head nodding were the most common signs.37 Therefore, many different types of seizure semiology may indicate TLE; conversely, absence of clinical findings typical of older children and adults should not rule out the diagnosis because semiology can represent spread to extratemporal regions (i.e., rather than origin from the mesial temporal region).38
Adults with MTS often have memory impairment specific to the hemisphere involved (i.e., verbal memory impairment with dominant hemisphere disease and nonverbal learning impairment in nondominant MTS). However, children tend to have less-specific neuropsychological deficits with impairment in long-term memory as well as both verbal and nonverbal learning.39 Patients with evidence of early bilateral MTS are at increased risk for more severe impairments in learning and memory.40
Evaluation
Detailed neurological examination should focus on evidence of memory and language dysfunction and additional signs of focal neurological deficits. The most frequently reported neurological abnormality in MTS patients is a mild contralateral facial paresis.41,42 The standard of care in evaluating a patient for the cause of a first seizure is to obtain a routine 30-minute EEG.43,44 In adults, the first routine EEG reveals epileptiform abnormalities in approximately 23% of patients.44
Electroencephalography and Electrocorticography
The interictal EEG in patients with suspected MTS often reveals unilateral or bilateral independent anterior temporal sharp waves and spikes ( Fig. 16.1A ).45–47 These epileptiform discharges may be better detected with inclusion of zygomatic or sphenoidal electrodes in adults, although noninvasive cheek electrodes are just as sensitive in detecting spikes.48 Invasive electrodes are not routinely used in the pediatric age group. Temporal intermittent rhythmic delta activity over the affected region is also highly suggestive of MTS.49,50 The typical ictal pattern consists of θ (5–7 Hz) to low a (8–9 Hz) frequency rhythmic sharp activity originating over the anterior temporal region either at the time of ictal onset (initial focal onset) or within 30 s of ictal onset (delayed focal onset)51,52 ( Fig. 16.1B ). In children, the initial ictal pattern is often preceded by a brief period of low voltage fast activity and can involve more diffuse generalized or bilateral activity.33,37
Patients with ictal and interictal patterns on scalp recording that are inconclusive or with no evidence of MTS on routine neuroimaging may require intracranial monitoring with subdural grid, strips, or depth electrodes to further differentiate MTS from a neocortical or extratemporal seizure foci. Studies reviewing these recordings have shown that patients with clear radiographic hippocampal sclerosis can have seizure foci distant from the hippocampus, including the temporal pole,53 amygdala,54 or perisylvian cortex.55
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