Surgically Remediable Syndromes

Jerome Engel Jr.

Gregory D. Cascino

W. Donald Shields

Introduction

The safety and efficacy of surgical treatment for epilepsy have improved greatly in recent years as a result of major advances in diagnostic technology, particularly long-term electroencephalographic (EEG) monitoring and neuroimaging, as well as refinements in surgical procedures.²¹^,²⁴^,³²^,⁵⁶ The vast majority of patients can undergo surgical intervention without the need for chronic invasive recordings, which contributes greatly to a decrease in morbidity, mortality, and cost, and more accurate localization of the epileptogenic region has resulted in better surgical results, leaving 80% to 90% seizure-free in some series of carefully selected patients. These developments have led to an important conceptual advance in epilepsy surgery: The view that surgical intervention need not always be considered a therapy of last resort but, rather, an early treatment of choice for certain well-defined surgically remediable syndromes.²³^,²⁴^,²⁹ Surgically remediable epilepsy syndromes are disorders for which (a) the pathophysiology is understood; (b) the natural history is reasonably well known to be medically refractory or even progressive once the major first-line antiepileptic drugs (AEDs) fail; (c) presurgical evaluation can be accomplished noninvasively; and (d) surgery offers an excellent chance that disabling seizures will be completely eliminated.

The prototype of a surgically remediable syndrome is mesial temporal lobe epilepsy (MTLE), the form of temporal lobe epilepsy (TLE) that is often, but not always, associated with hippocampal sclerosis (HS).⁹¹^,⁹² Neocortical epilepsies caused by well-circumscribed solitary lesions¹³ and a variety of unilateral but relatively diffuse hemispheric disorders in infants and young children⁷⁸ are also in this category.

Arguments for Early Intervention

Uncontrolled epileptic seizures can severely impair activities of daily living. In MTLE, complex partial seizures are usually prominent in adolescence and early adulthood, when they disrupt schooling and the acquisition of the social and vocational skills necessary to lead a normal, productive, and satisfying life. Frequent seizures in infants and young children can have an even more disastrous effect on psychomotor development. The avoidance of irreversible psychosocial consequences of epilepsy, therefore, is a strong argument for early intervention in surgically remediable epilepsies. There is, however, additional evidence for direct deleterious effects of certain seizure types on the brain.⁸⁴ The progressive nature of epilepsy, although controversial, has been well demonstrated by phenomena such as kindling³⁸ and secondary epileptogenesis,⁵⁹ seen in experimental animal models. If similar processes exist in human epilepsy, they could result in a worsening of epileptic seizures, manifested as more frequent or more severe seizures, more medically refractory seizures, or perhaps even surgically refractory seizures. Enduring disruption of normal cerebral function and the appearance of interictal behavioral disturbances could also result from these progressive changes or appear as a side effect of those natural, protective seizure-suppressing mechanisms that develop to maintain the interictal state.²⁶

What is the evidence that progressive processes exist in the surgically remediable epileptic syndromes? In MTLE, seizures usually do not become medically refractory until many years after onset of the habitual events,⁸ and interictal behavioral disturbances are reported to be common in this disorder.²⁵^,⁹² Furthermore, some evidence suggests that surgery is less likely to produce complete freedom from seizures when performed late in the course of the disorder.²⁷ In lesional neocortical epilepsy (LNE), late surgical intervention also decreases prognosis for elimination of all ictal events.⁶⁰ In both these disorders, cognitive function improves following surgical treatment, particularly the material-specific memory function of the temporal lobe contralateral to an anterior temporal lobectomy.⁷⁰ Reversal of developmental delay by surgery for diffuse hemispheric epileptogenic disturbances in infants and young children⁷⁹ is particularly remarkable because children with these disorders who continue to have seizures almost invariably develop mental retardation and often require institutional care. These observations strongly support the view that at least some types of epileptic seizures can themselves induce progressive cerebral dysfunction and provide a strong case for early surgical intervention.²⁵

Because complete freedom from seizures early in the course of the disorder can prevent the development of disabling psychosocial consequences of epilepsy as well as interictal behavioral disturbances that might result directly from seizures, early surgical intervention for the surgically remediable syndromes offers the best opportunity for achieving a normal postoperative quality of life (88). Also, because the cost of presurgical evaluation and of the surgery itself is the same whether performed early or late, and early intervention is most likely to eliminate future medical expenses and result in an independent, tax-paying individual, this approach is certainly more cost-effective.

To practice early intervention, however, it is necessary to redefine the concept of medical intractability, and this requires further study. At present, for adolescents and adults, failure of two or perhaps three of the most appropriate AEDs as monotherapy at maximum tolerable doses seems to be an adequate definition, whereas the use of second-line medications and multiple-drug combinations would unnecessarily delay a potentially definitive therapy. The need for rapidly establishing surgical candidacy may be even more urgent for infants and young children with very frequent seizures and developmental
delay. Specific ages at which a timely decision might be particularly critical are (a) 5 to 7 years, when the plastic properties of the developing brain begin to decrease sufficiently to cause concern that hemispherectomy or multilobar resection will cause additional neurologic disability, particularly for language; and (b) early adolescence, when continuing seizures have a negative effect on social development and academic achievement.

Recognition that a patient might have a surgically remediable epilepsy syndrome as soon as possible after the onset of seizures and expedient trials of the most effective AEDs to establish medical intractability in a timely manner provide the best opportunity for early surgical intervention and optimum postoperative results. To achieve this goal, it is necessary for primary care physicians and practicing neurologists in the community to know how to identify these patients so that crucial years are not lost pursuing ineffective pharmacotherapy. The remainder of this chapter is devoted to the best-defined surgically remediable epilepsy syndromes.

Specific Syndromes

Syndromes to be Excluded from Early Surgical Intervention

It is important to note at the outset that many epilepsy disorders that are not surgically remediable syndromes can be easily identified early in their course. Obviously, patients with benign idiopathic epilepsies are not candidates for surgical treatment; most of these disorders are characterized by generalized seizures that are easily controlled by medication. An old argument against early surgical treatment for TLE in children, however, was that temporal lobe seizures often disappear in adolescence. Now that the syndrome of benign childhood epilepsy with centrotemporal spikes and related disorders can be readily distinguished from TLE,⁵⁰^,⁵¹ it is believed that most patients previously thought to recover spontaneously from TLE⁵²^,⁵³^,⁵⁴ actually had idiopathic localization-related epilepsy. Because the clinical and EEG presentation is so characteristic, and the seizures are so responsive to medication, children with idiopathic localization-related epilepsy that will resolve spontaneously are easily excluded from a presurgical population. At the other extreme are patients with clearly intractable seizures who do not meet the criteria for having a benign idiopathic syndrome, but who have either no abnormalities on structural or functional neuroimaging or diffuse bilateral lesions.

These patients may well ultimately become surgical candidates; however, if the epileptogenic region can be defined only electrographically, the surgical results are not as good as for patients with surgically remediable syndromes, and the need for invasive monitoring greatly increases the risk and cost of presurgical evaluation.⁸⁷ It is reasonable, therefore, to pursue additional AEDs alone and in combination for much longer periods before such patients are referred for surgical treatment.

Mesial Temporal Lobe Epilepsy

Most patients considered candidates for surgical treatment today have localization-related symptomatic epilepsies, with seizures resulting from an epileptogenic lesion that is limited to one hemisphere and is potentially resectable. Lesions in the limbic system, particularly those involving mesial temporal structures, give rise to complex partial seizures with a relatively characteristic semiology as a result of preferential propagation patterns that are reasonably well understood. Because anterior temporal resections are the most commonly performed surgical treatment for epilepsy, a considerable amount of basic research has been done on mesial temporal tissues taken from patients with medically refractory complex partial seizures, and a common pathophysiologic substrate has been described for many. This consists of HS,⁷ the most common lesion found in patients with epilepsy.⁷⁵ Most workers now recognize a syndrome of MTLE with HS (MTLE-HS) that has characteristic clinical features, often gives rise to medically refractory complex partial seizures, and responds well to surgical intervention (Table 1).²³^,⁹¹^,⁹² Sixty percent to 80% of patients with this disorder can expect to become free of disabling seizures following anterior temporal lobectomy.³¹^,³²^,⁹⁰

HS is characterized by a specific pattern of cell loss and neuronal reorganization that is presumed to underlie the epileptogenicity.⁶ Although structural changes are concentrated in the hippocampus, amygdala, and adjacent limbic cortex, functional disturbances are much more extensive. Hypometabolism on positron emission tomography (PET) usually involves the entire temporal lobe and frequently includes the ipsilateral thalamus and, less often, other ipsilateral cortical and subcortical structures,³⁰^,⁴⁰ and contralateral mesial temporal abnormalities are evidenced by the common appearance of contralateral interictal EEG spikes³¹ and material-specific memory disturbances.⁶⁹ It is unclear to what extent these abnormalities reflect mechanisms that contribute to epileptogenicity and to what extent they reflect disruption of normal function caused by propagation of epileptic activity. Although merely resecting the anterior and mesial portions of the temporal lobe, and in some cases only the amygdala and hippocampus, can abolish disabling seizures, auras tend to persist in this group of patients, supporting a view that the epileptogenic region is widespread.⁹¹

The fact that habitual seizures in MTLE-HS most commonly begin within the first decade of life and are usually responsive to medication for several years, with events characteristically becoming refractory to medication in adolescence,⁸ suggests some progressive nature of the epileptogenic process. The commonly encountered family history and presence of microdysplasias in this disorder suggest a familial and/or congenital predisposition to the development of HS, given a specific cerebral insult early in life.⁹¹ The frequent occurrence of prolonged febrile convulsions can be seen as evidence of a preexisting epileptic diathesis but also could serve as a HS-inducing insult. Other early insults are common in this disorder,⁵⁷ and it is conceivable that, in some children, seemingly innocuous events, such as common childhood viruses, are sufficient to set the epileptogenic process in motion. The resultant characteristic cell loss and neuronal reorganization are accompanied by the development of a propensity to generate spontaneous epileptic seizures. This presumably takes many years, accounting for the latent period between the initial insult and the onset of habitual ictal events.³⁷ It would be unreasonable to assume, however, that this epileptogenic process would suddenly cease at this point; rather, it is more logical to suggest that these underlying aberrant neuronal changes continue to some extent and account for a worsening of the epileptic condition and the eventual appearance of medically refractory seizures.²⁸ Similar progressive changes might also account for the even later appearance of interictal behavioral disturbances.²⁶ For this reason, and because 60% to 80% of patients can expect to become seizure-free following appropriate anterior mesial temporal lobe resection, early surgical intervention as soon as monotherapy with the two or three preferred AEDs has failed would offer the best opportunity for relief of seizures, complete psychosocial rehabilitation, and a normal, productive lifestyle.²³^,²⁴^,²⁵^,³²

Table 1 The Syndrome of Mesial Temporal Lobe Epilepsy with Hippocampal Sclerosis (MTLE-HS)^a

History

Increased incidence of complicated febrile convulsions

Increased incidence of a family history of epilepsy

Onset in latter half of first decade of life

Auras common and occur in isolation

Secondarily generalized seizures occur infrequently

Seizures often remit for several years until adolescence or early adulthood

Seizures often become medically intractable

Interictal behavioral disturbances can occur (most commonly depression)

Clinical seizure

Aura is usually present: most common is epigastric rising, often other autonomic or psychic symptoms, with emotion (e.g., fear), can be olfactory or gustatory sensation (several seconds)

Complex partial seizure: often begins with arrest and stare, oroalimentary automatisms and complex automatisms common; posturing of one upper extremity can occur contralateral to the ictal discharge (1 to 2 min)

Postictal phase: usually includes disorientation, recent memory deficit, amnesia for the event, and dysphasia if seizures begin in the language-dominant hemisphere (several minutes)

Neurologic examination

Usually normal

Can have recent memory deficit

EEG

Unilateral or bilateral independent anterior temporal spikes, maximum amplitude in basal electrodes

Can have intermittent or continuous rhythmic slowing in one mesial temporal area

Extracranially recorded ictal activity appears only with complex partial symptoms, usually initial or delayed focal onset pattern of 5- to 7 per second rhythmic activity, maximum amplitude in one basal temporal derivation

Depth electrode recorded ictal onset most often high-amplitude rhythmic spikes or sharp waves, less commonly low-voltage fast or suppression

Propagation to contralateral side is slow (>5 sec, but may be minutes) or does not occur at all

Focal functional deficits

Usually temporal lobe hypometabolism on interictal FDG-PET, often involves ipsilateral thalamus and basal ganglia

Usually temporal lobe hypoperfusion on interictal SPECT and characteristic pattern of hyper- and hypoperfusion on ictal SPECT

Usually material-specific memory disturbances on neuropsychological testing and amnesia with contralateral intracarotid sodium amobarbital injection

Mesial temporal EEG slowing and attenuation of normal rhythms can be seen with scalp/sphenoidal electrodes but more common with depth electrodes; exacerbated by intravenous pentobarbital test

Structural imaging

Usually has small hippocampus on one side on MRI

Usually has increased hippocampal T2 signal on one side on MRI

Can have small temporal lobe on one side

Can have enlarged temporal horn on one side

Can have reduced NAA on MRS

Pathophysiology

Hippocampal sclerosis (>30% cell loss with specific patterns)

Sprouting of dentate granule cell mossy fibers

Selective loss of certain hilar neurons (somatostatin- and NPY-containing cells)

Gliosis

Dentate laminar dispersion

Hamartomas and heterotopias can occur as “dual pathology”

Microdysgenesis common

Seizures usually originate in sclerotic hippocampus, but much larger area appears to be included in the epileptogenic region

Features that place diagnosis in doubt

History of severe head trauma, encephalitis, or other specific causal events after the age of 5

Focal motor or specific sensory symptoms at seizure onset or postictally

Interictal focal neurologic deficits other than memory disturbance

Marked cognitive impairment on neuropsychological testing

Bilaterally synchronous, generalized, or extratemporal focal EEG spikes

Diffuse or extratemporal focal EEG slowing

Cerebral lesion other than hippocampal sclerosis on MRI

Modified from Engel J Jr. Update on surgical treatment of the epilepsies. Neurology. 1993;43:1612–1617, with permission.

MTLE-HS can usually be suspected early in the course of this disorder from the typical history and characteristic simple and complex partial seizures (see Table 1). Referral to an epilepsy surgery program should be made once habitual seizures become disabling and are resistant to at least two appropriate AEDs at maximum tolerable doses. At most

epilepsy surgery centers, demonstration with long-term EEG video monitoring that the habitual seizures originate electrographically from one mesial temporal area and either magnetic resonance imaging (MRI) evidence that the hippocampus on that side is damaged or PET evidence that the temporal lobe on that side is hypometabolic is sufficient to recommend surgery, provided there are no conflicting findings such as atypical initial seizure semiology, other suspicious lesions on MRI, or evidence of a nonconcordant localized functional deficit. Surgical treatment for MTLE-HS, as well as MTLE due to most other causes, is particularly cost-effective because the presurgical evaluation can almost always be performed noninvasively, and the chances of restoring the patient to a completely normal lifestyle are high, making this an ideal surgically remediable syndrome.

Lesional Focal Epilepsies

The pathologic finding underlying the epileptogenic zone in approximately 30% of patients undergoing epilepsy surgery is a substrate-directed abnormality, such as a tumor or vascular malformation.¹³ Identification of the epileptogenic lesions by MRI is imperative in patients with pharmacoresistant seizures because of the demonstrated beneficial effect of surgical treatment.¹¹^,¹² MRI has increased the identification of structural alterations in patients being considered for surgical treatment of intractable focal epilepsy.¹²^,⁷⁴ Surgically remediable epilepsy syndromes associated with substrate-directed focal epilepsy includes patients with MTLE related to HS (see previous section) and lesional epilepsy syndromes.¹³^,⁹⁰ Selected patients with lesional focal epilepsy may be highly favorable candidates for surgical treatment. The surgical pathologies in patients with lesional focal epilepsy include primary brain neoplasm, vascular anomaly, and a malformation of cortical development (MCD).¹³ The common tumors identified at the time of surgical excision of the epileptogenic cortex include low-grade gliomas, gangliogliomas, dysembryoplastic neuroepitheliomas (DNETs), and mixed glial neoplasms.¹¹^,¹²^,⁶²^,⁸² The cavernous hemangioma with remote hemorrhage is the most frequently resected vascular anomaly in patients with medically refractory focal epilepsy.¹³ Focal cortical dysplasia is an increasingly important etiology of lesional focal epilepsy because of the increased diagnostic yield of structural neuroimaging techniques and the performance of epilepsy surgery in younger patients.⁶³^,⁸¹ The outcome of epilepsy surgery depends on the pathology and location of the epileptogenic lesion.¹³ Approximately 80% of patients with a low-grade glial neoplasm, ganglioglioma, DNET, or cavernous hemangioma are rendered seizure-free following surgical treatment. Resection of a focal MCD in individuals with lesional focal epilepsy is less effective in reducing seizure tendency.¹⁴^,⁶³^,⁸¹ Patients with MTLE are more favorable candidates to achieve a seizure remission than are those individuals with neocortical (mainly frontal lobe) focal seizures.⁶²^,⁹⁰^,⁹¹

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