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Neuroimaging in Epilepsy$

Harry Chugani, MD

Print publication date: 2010

Print ISBN-13: 9780195342765

Published to Oxford Scholarship Online: January 2011

DOI: 10.1093/acprof:oso/9780195342765.001.0001

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Positron Emission Tomography: Brain Glucose Metabolism in Pediatric Epilepsy Syndromes

Positron Emission Tomography: Brain Glucose Metabolism in Pediatric Epilepsy Syndromes

Chapter:
(p.156) Chapter 10 Positron Emission Tomography: Brain Glucose Metabolism in Pediatric Epilepsy Syndromes
Source:
Neuroimaging in Epilepsy
Author(s):

Aimee F. Luat

Harry T. Chugani

Publisher:
Oxford University Press
DOI:10.1093/acprof:oso/9780195342765.003.0010

Abstract and Keywords

The advent of positron emission tomography (PET) scanning using 2-deoxy-2-[18F] fluoro-D-glucose (FDG) has significantly improved our understanding of the pathomechanisms of different pediatric epilepsy syndromes. Furthermore, it has dramatically altered our management approach of certain intractable epilepsy syndromes, such as infantile spasms. Glucose metabolism PET scanning has assumed an important role not only in the identification and localization of epileptogenic cortex, but also in assessing the functional integrity of the entire cerebral hemisphere, thereby providing useful diagnostic and prognostic information, including the suggestion of underlying neurometabolic or neurogenetic disorders which may preclude epilepsy surgery. In certain progressive epilepsy syndromes like Rasmussen encephalitis and Sturge-Weber syndrome, PET scanning also may be used to assess disease progression. In this chapter, we discuss the relevant role of brain glucose metabolism PET in understanding the pathogenesis of pediatric epilepsy syndromes with regard to diagnosis and treatment.

Keywords:   pediatric epilepsy, epilepsy syndromes, brain glucose PET scanning, intractable epilepsy, epilepsy surgery

Introduction

Epilepsy syndrome is defined by the International League Against Epilepsy (ILAE) as a complex of signs and symptoms that characterize a unique epilepsy condition with different etiologies (Engel 2001). Syndrome classification of epilepsy is based on the cluster of clinical features, including age of onset, seizure types, and interictal as well as ictal electroencephalography (EEG) findings. Structural imaging, particularly magnetic resonance imaging (MRI), is the primary neuroimaging modality used in the evaluation and management of epilepsy, and this has been reviewed elsewhere in this volume. However, there are several epilepsy syndromes where MRI is normal, is non-specific, or provides limited information, and in these instances functional neuroimaging assumes an important role.

The measurement of cerebral glucose metabolism using 2-deoxy-2- [18F]fluoro-D-glucose (FDG) with positron emission tomography (PET) has dramatically altered our understanding and management approach to some childhood epilepsy syndromes. Indeed, in infants and children with intractable epilepsy, glucose metabolism PET scanning has assumed an important role in localizing epileptogenic cortex for surgical resection even in syndromes where the epilepsy was previously believed to be primary generalized and not amenable to cortical resection. When localization of the epileptogenic zone is apparent, FDG PET can also assess the functional integrity of brain regions outside of the suspected epileptogenic zone as well as the contralateral hemisphere, thereby providing useful prognostic information. Conversely, glucose metabolism PET studies may suggest the presence of an underlying neurogenetic or metabolic condition and preclude further epilepsy surgery evaluation. This chapter reviews the role of cerebral glucose metabolism PET imaging in various childhood epilepsy syndromes with respect to patterns of glucose utilization to provide a better understanding of underlying mechanisms, surgical treatment, and prognostic implications. PET applications of temporal lobe epilepsy (Chapter 8) and extratemporal lobe epilepsy (Chapter 9) are discussed (p.157) elsewhere in this volume and will not be included in the present chapter.

Neonatal Seizures

The incidence of neonatal seizures has been reported to range from 1.8 to 3.5 per 1,000 live births (Lanska et al. 1995; Saliba et al. 1999). Premature and low birth weight infants have a much higher rate of neonatal seizures compared to full-term and normal birth weight infants (Lanska et al. 1995). The etiologies of seizures in the neonatal period are diverse and are usually due to symptomatic causes, which include hypoxic ischemic encephalopathy, stroke, infection, cerebral malformations, and neurocutaneous and neurometabolic disorders. The recognition of the underlying etiology of neonatal seizures is important because some etiologies indicate specific treatments that when implemented early in the course may improve neurologic outcome.

Neuroradiologic investigations are an integral part of the diagnostic approach to uncover the causes of neonatal seizures. Neuroimaging is routinely performed to exclude the presence of brain pathology or lesions such as cortical malformations and stroke. Cranial ultrasound, MRI, and computed tomography (CT) scanning are among the most frequently used neuroimaging tests in neonates. Cranial ultrasound is readily available in most neonatal intensive care units (NICUs) and has been used as a first-line neuroimaging tool in the evaluation. However, it is not sensitive enough to detect certain brain lesions such as stroke and cortical malformations. In addition, the test tends to be somewhat dependent on the skill of the technologist performing the test. If the cranial ultrasound is normal, further testing using cranial CT or MRI should be performed. However, in neonates, certain brain malformations (e.g., some cortical dysplasias) may still not be detectable even when using high-resolution MRI.

Glucose metabolism PET studies in neonates and infants can provide important localizing information in cases of intractable seizures by detecting subtle malformations of cortical development at a time when they are not yet apparent on the MRI scan because of the relatively low state of myelination. However, due to the normal developmental changes of brain glucose metabolism in the first year of life (Chugani et al. 1987), these changes must be taken into account and the PET scans cautiously interpreted (Fig. 10.1).

At Children’s Hospital of Michigan, a microPET scanner originally intended for scanning monkeys was adapted for human use and placed in the NICU. This microPET Focus 220 positron emission tomograph (Concorde Microsystems, Knoxville, TN) (Fig. 10.2)

                   Positron Emission Tomography: Brain Glucose Metabolism in Pediatric Epilepsy Syndromes

Figure 10.1 Patterns of cerebral glucose utilization during neonatal and infancy periods shown on PET scans. In the neonate, glucose metabolism is highest in sensorimotor cortex, thalamus, brain stem, and cerebellar vermis. In higher-resolution scans, medial temporal lobe regions also show relatively high glucose metabolism. Note the relatively low glucose metabolic rates in most of the cerebral and cerebellar cortex at this stage. By 3 months, there is increased glucose utilization in parietal, temporal, and occipital cortex, as well as cerebellar hemispheres. By 8 months, glucose utilization has increased in the lateral portion of frontal cortex much more than in the medial portion. The pattern of cerebral glucose utilization in a 1-year-old infant resembles that of an adult.

(p.158)
                   Positron Emission Tomography: Brain Glucose Metabolism in Pediatric Epilepsy Syndromes

Figure 10.2 The Focus 220 microPET scanner located inside the neonatal intensive care unit at Hutzel Women’s Hospital in the Detroit Medical Center, Wayne State University. This scanner can also be used to scan larger infants weighing less than 15 kilograms.

                   Positron Emission Tomography: Brain Glucose Metabolism in Pediatric Epilepsy Syndromes

Figure 10.3 FDG PET scan using the Focus 220 microPET scanner from a 36-week gestational age newborn showing left frontal hypometabolism (arrows) following intracranial hemorrhage. Note the high spatial resolution capable of identifying even brain stem nuclei. Note also functional activity in medial temporal regions.

operates exclusively in 3D mode and produces images with a reconstructed isotropic resolution of 2 × 2 × 2 mm at full-width-half-maximum. The port diameter of this system is 22 cm, with an axial field-of-view of 8 cm. The gantry is connected to a Pentium PC for data reconstruction, display, and archiving. Because the scanner is housed in the NICU, minimal transport of the newborn is necessary and the NICU nurse continues to care for the infant during the study. If necessary, the infant is fed 2 hours prior to the PET scan. A venous catheter is typically already in place in these infants and provides the route of radiotracer administration. We do not sedate these babies during the time required to acquire the images since they typically lie quite still after being wrapped in a blanket. After reconstruction of the raw data, images are transferred to the main PET Center using the local area network for further processing.

The PET studies of cerebral glucose metabolism in neonates using the microPET scanner have replicated our previous findings indicating the very early functional maturation of sensorimotor cortex, thalamus, brain stem, and cerebellar vermis (Chugani et al. 2005). However, in addition to these, increased glucose metabolism can also be noted in limbic structures such as amygdala, even in prematurely born babies (Fig. 10.3) (Chugani et al. 2005). As indicated above, these maturational changes must be taken into account when interpreting potential abnormalities. For example, a frontal lobe epileptic focus might be missed when an interictal glucose metabolism PET scan is performed prior to about 8 to 12 months of age, since frontal lobe glucose metabolic activity is still undergoing a maturational increase. In fact, in the neonatal period, interictal glucose metabolism PET studies are of limited value in seizure patients because of the normally very low glucose metabolism in most of the cerebral cortex at this age. In contrast, ictal scans are often highly localizing and may even reveal areas of seizure propagation in newborns.

Ohtahara Syndrome

Ohtahara syndrome, also called early infantile epileptic encephalopathy with suppression bursts, is the earliest form of epileptic encephalopathy (Ohtahara 1978). The syndrome is characterized by the onset in early infancy (within the first 3 months, mainly in the first 10 days of life) of intractable epilepsy, particularly tonic spasms, and a diffuse burst suppression pattern on the EEG. In addition to tonic seizures, partial seizures and hemiconvulsions are observed in between a third and a half of these infants. Although the majority of cases of Ohtahara syndrome are associated with structural brain abnormalities, infants with various other underlying disorders can also meet the criteria for Ohtahara syndrome. Indeed, Ohtahara’s series included cases of Aicardi syndrome, porencephaly, hydrocephalus, hemimegalencephaly, and lissencephaly.

There is no specific pattern of abnormal glucose metabolism on PET scans for Ohtahara syndrome. Figure 10.4 shows the MRI and FDG PET findings of an 8-day-old infant who presented with Ohtahara syndrome. MRI showed bilateral perisylvian and perirolandic polymicrogyria, left more involved than right. Ictal FDG PET showed increased glucose metabolism in the left frontal and left medial temporal areas, as well as retrosplenial portion of the cingulate cortex. Hmaimess et al. (2005) have reported a case of Ohtahara syndrome associated with left parieto-occipital hemimegalencephaly. Glucose metabolism PET scan showed left posterior hypermetabolism. (p.159)

                   Positron Emission Tomography: Brain Glucose Metabolism in Pediatric Epilepsy Syndromes

Figure 10.4 An 8-day-old neonate with Ohtahara syndrome whose MRI shows bilateral perisylvian cortical dysplasia (polymicrogyria), which is more extensive on the left side. Ictal FDG PET scan shows increased glucose metabolism in the left frontal cortex (arrows), left thalamus, and left retrosplenial cingulate cortex. EEG during the scanning showed frequent sharp and wave activities in the left frontal and temporal areas, and occasionally in the right temporal region. Clusters of tonic spasms were captured, during which the EEG showed lateralization to the left hemisphere.

Left transcortical perisylvian resection led to resolution of the seizures and resulted in developmental progress. The report suggests the need to seek for an underlying unilateral pathology in Ohtahara syndrome since epilepsy surgery may be a promising treatment option in at least some cases.

Epileptic Spasms

Epileptic spasms are seizures characterized by clusters of short contractions typically involving the head, trunk, and extremities. Previously called infantile spasms, epileptic spasms is the preferred term because they can occur or persist beyond infancy. Epileptic spasms can occur in isolation or as part of West syndrome, which is the triad of epileptic spasms, an EEG pattern of hypsarrhythmia, and developmental arrest. When epileptic spasms are associated with an underlying condition (e.g., tuberous sclerosis, Down syndrome, brain injury), they are referred to as symptomatic, but when no underlying etiology can be determined, the term cryptogenic is applied to signify that there probably is an underlying hidden cause, albeit elusive. Rare cases have been described where there is truly no underlying etiology and the spasms are a transient manifestation of a neurophysiologic immaturity that resolves readily with treatment such as adrenocortical hormone (ACTH) or vigabatrin without any subsequent adverse outcome (“idiopathic” epileptic spasms) (Dulac et al. 1986, 1993).

Epileptic spasms, because of the bilateral and relatively symmetric clinical semiology, have traditionally been classified as a form of generalized seizure. However, following the report of Chugani et al. (1990), it became apparent that in a subset of patients, epileptic spasms may be a form of secondary generalized seizure propagating from cortical lesions not always apparent on MRI but readily appreciated on FDG PET scans. In that report, unilateral cortical areas of glucose hypometabolism were demonstrated in five children with presumed cryptogenic intractable epileptic spasms (normal MRI in 4/5). Four of these five children underwent resection of the cortical areas of glucose hypometabolism, guided by intracranial electrocorticography, resulting in seizure freedom or improvement of seizure control. Neuropathology of the resected brain tissue showed cortical dysplasia. A subsequent study on a large number of patients with spasms (n = 140) found that among the 97 cases classified as cryptogenic, a single cortical focus of abnormal glucose metabolism (unilateral hemispheric or focal) was identified in 30 and multifocal abnormalities were found in 62 (Chugani et al. 1996). These unifocal and unilateral PET abnormalities (Fig. 10.5A,B) are believed to be due to underlying cortical dysplasia. The recognition that a subset of patients with intractable epileptic spasms may harbor potentially resectable focal areas of cortical dysplasia has led to the challenge of pediatric epilepsy surgery centers to identify these surgical candidates to improve their outcome. Indeed, following the original report of Chugani et al. in 1990 (p.160)

                   Positron Emission Tomography: Brain Glucose Metabolism in Pediatric Epilepsy Syndromes

Figure 10.5 Four different patterns of cortical glucose hypometabolism in infants with epileptic spasms. (A) Unifocal and (B) unilateral cortical hypometabolism (surgical candidates), 20% (black arrows). (C) Multifocal cortical hypometabolism, 65% (dotted arrows). (D) Bitemporal cortical hypometabolism, 10%. (E) Diffuse cortical hypometabolism, 5%.

and a subsequent study in 1993 involving 23 surgical cases (Chugani et al. 1993), several investigators have replicated the finding that surgical resection of the cortical abnormality in selected patients with intractable spasms can provide seizure control (Kramer et al. 1997; Sugimoto et al. 1999; Wyllie et al. 1996, 1998).

Unfortunately, about 65% of children with cryptogenic epileptic spasms demonstrate multifocal areas of glucose hypometabolism, an additional 10% show bitemporal areas of glucose hypometabolism, and 5% show bilateral diffuse cortical hypometabolism (Fig. 10.5C–E). In these infants, epilepsy surgery is usually not an option, although in some multifocal cases we have performed a “palliative” resection to improve the patient’s quality of life if the seizures are intractable and very frequent and the vast majority emanate from one general region.

Based on FDG PET studies, our insights on the pathophysiology of epileptic spasms have greatly expanded. Ictal FDG PET scans performed during prolonged clusters of spasms or during frequent interictal spiking on the EEG have shown bilateral symmetric hypermetabolism of the lenticular nuclei and brainstem, in addition to focal area of cortical hypo- or hypermetabolism, thus suggesting that the spasms are initiated by a primary cortical epileptic focus that interacts with subcortical and brainstem structures (Fig. 10.6A) (Chugani et al. 1992). This finding led to the proposal of a neuronal circuitry illustrated in Figure 10.6B. Thus, it is proposed that during a critical stage of brain development (beginning at about 3 months, when cortical maturation becomes evident on FDG PET scans), the primary cortical focus interacts through its epileptic discharges with brainstem structures, particularly the raphe nuclei, which have strong cortical projections. The raphe-cortical and cortico-cortical propagation may be responsible for the EEG feature of hypsarrhythmia. The raphe nuclei also have projections to the striatal region (bilateral putamen), and these pathways may activate descending spinal pathways bilaterally to result in the bilateral and relatively symmetric clinical semiology of epileptic spasms.

As previously mentioned, about 10% of all infants with cryptogenic spasms show bilateral temporal lobe hypometabolism on their PET scans (Fig. 10.5D). These children show a distinct clinical phenotype characterized by severe developmental delay (particularly in the language domain) and autism. The PET scan may also reveal bilateral frontal cortical hypometabolism, and occasionally generalized cortical hypometabolism, with or without associated cerebellar involvement (p.161)

                   Positron Emission Tomography: Brain Glucose Metabolism in Pediatric Epilepsy Syndromes

Figure 10.6 (A) FDG PET (ictal PET) scan obtained during a prolonged cluster of spasms showing bilateral symmetric hypermetabolism of the lenticular and brain stem nuclei in addition to a focal area of cortical hypermetabolism, suggesting that spasms are initiated by a primary cortical epileptic focus that interacts with the subcortical and brain stem structures. (B) Schematic representation of brain pathways hypothesized in infantile spasms, with PET images showing increased glucose metabolism in activated regions (from Chugani et al. 1992). Pathway 1 (green). “Nociferous” influence of abnormal cortical region (red) on brain stem (raphe area). Pathway 2 (yellow). Raphe-striatal pathway, serotonergic (5HT1D), under tonic control by corticosteroids. Pathway 3 (blue). Generation of hypsarrhythmic pattern. Pathway 4 (purple). Spinal cord propagation (direct or indirect) and lenticular nuclei involvement results in the generation of clinical spasms. Pathway 5 (white). Surgical resection of the primary cortical abnormality abolishes activation of the circuitry.

(Fig. 10.5E). This type of pattern is not suggestive of an underlying lesional etiology but, rather, may indicate an underlying genetic/metabolic condition and represents a heterogeneous group. When this pattern is encountered, more detailed metabolic and genetic studies (e.g., chromosomal microarray analysis) should be performed and the idea of cortical resection should be abandoned. Thus, in patients with cryptogenic epileptic spasms, FDG PET scans are a useful guide into optimal clinical management.

Tuberous Sclerosis Complex

Tuberous sclerosis complex (TSC) is a multisystem autosomal dominant disorder characterized by the presence of multiple hamartomas in various organs of the body, including the brain. It is caused by mutation of one of two tumor suppressor genes: TSC 1 on chromosome 9q34 (Fryer et al. 1987; van Slegtenhorst et al. 1997) or TSC 2 on chromosome 16p13.3 (Kandt et al. 1992); these genes encode for hamartin and tuberin, respectively. Epilepsy is its most common neurologic presentation, occurring in 80% to 90% of TSC patients, and seizures in TSC often become refractory to medical treatment. Cortical tubers have been implicated as the sites of epileptogenesis in TSC (Curatolo and Cusmai 1988; Cusmai et al. 1990). However, not all tubers are epileptogenic, as indicated by surgical outcome studies showing good seizure outcome following resection of the suspected epileptogenic tubers and leaving the non-epileptogenic ones in place (Jansen et al. 2007; Kagawa et al. 2005; Lachwani et al. 2005; Madhavan et al. 2007; Teutonico et al. 2008; Weiner et al. 2006). Over the past several years, epilepsy surgery in TSC has become an important treatment option, although the identification of the epileptogenic tuber can be a challenge because it may be difficult to identify amid the presence of multiple bilateral lesions.

The application of multimodality neuroimaging is important in the presurgical evaluation of TSC patients. FDG PET can detect small cortical tubers that are not visualized on T2-weighted MRI but that can be observed on fluid attenuated inversion recovery (FLAIR) images; however, the area of glucose hypometabolism is usually larger than the lesions seen on MRI (Asano et al. 2000a, Asano et al. 2000b). Furthermore, glucose metabolism PET allows detection of not only the cortical tubers, but also of dysplastic cortex, which may appear normal on MRI. Although FDG PET cannot distinguish between epileptogenic and non-epileptogenic tubers, it can assess the full extent of functional abnormalities in the brain and evaluate the integrity of cortex homotopic to a planned surgical resection (Asano et al. 2003), thereby predicting potential postoperative cognitive deficits. Typically, cortical tubers are depicted as multifocal areas of glucose hypometabolism (Asano et al. 2003; Rintahaka et al. 1997; Szelies et al. 1983), which is hypothesized to be due to the decreased number of neurons and simplified dendritic pattern within the tubers, and hence less requirement for glucose (Mata et al. 1980) (Fig. 10.7).

The application of glucose metabolism PET in TSC has also contributed to our understanding of the neurobehavioral phenotypes of TSC, including autism, attention-deficit/hyperactivity disorder, aggression, and cognitive impairment. Together with alpha[11C]methyl-L-tryptophan (AMT) PET (see Chapter 12 for the role of AMT PET in identifying epileptogenic tubers), these PET studies have expanded our understanding of the pathophysiology of autism in TSC, pointing to both cortical and subcortical dysfunction (Asano et al. 2001). The severity of language disturbance has been (p.162)

                   Positron Emission Tomography: Brain Glucose Metabolism in Pediatric Epilepsy Syndromes

Figure 10.7 (A) FDG PET scan of a 1-year-old boy with TSC 2 gene mutation and intractable epileptic spasms, showing multiple and bilateral areas of glucose hypometabolism (black arrows). (B) AMT PET scan of the same patient showing increased AMT uptake in the left frontal-parietal tuber (dotted arrow), but no other tubers. Left fronto-parietal resection provided seizure freedom (4 years follow-up).

correlated with bilateral temporal cortex glucose hypometabolism. Autistic features consisting of stereotyped behavior, impaired social interaction, and communication disturbance have been correlated with glucose hypermetabolism in the deep cerebellar nuclei and increased AMT uptake in the caudate nucleus. Furthermore, the presence of right-sided cerebellar lesions was associated with higher social isolation, and communicative and developmental disturbance when compared with left-sided cerebellar lesions (Eluvathingal et al. 2006).

Sturge-Weber Syndrome

Sturge-Weber syndrome (SWS) is a rare sporadic neurocutaneous syndrome characterized by facial cutaneous angioma (unilateral or bilateral “port-wine stains”) typically located in the distributions of the trigeminal nerve, associated with ipsilateral leptomeningeal angiomatosis, and congenital glaucoma. The angiomatous changes in SWS have been attributed to the failure of regression of the primitive embryonal vascular plexus on the cephalic portion of the neural tube (Di Rocco and Tamburrini 2006). Although the precise etiology of the dysregulated angiogenesis in SWS is still poorly understood, somatic mutation has been implicated based on cytogenetic and karyotype analyses of tissues from affected individuals (Huq et al. 2002). Similarly, tissue culture studies have demonstrated that fibronectin gene expression in fibroblasts derived from SWS port-wine tissue samples is increased (Comi et al. 2003; Zhou et al. 2009), suggesting that excessive expression of fibronectin may contribute to the dysregulated embryonal angiogenesis in SWS. The angioma may lead to venous stasis and thrombosis, resulting in hypoxia and chronic ischemia in the underlying cortical and subcortical areas with subsequent calcifications.

The clinical course of SWS is variable. It may be clinically static but can be a progressive neurologic condition leading to mental retardation, hemiplegia, visual deficit, and intractable epilepsy. Seizures are the most common feature. Indeed, 75% to 90% of children with SWS develop epilepsy.

Structural neuroimaging using CT and MRI helps to establish the diagnosis of SWS and define the extent of the angioma, which may involve the entire hemisphere or portions of the hemisphere (often posteriorly). CT scan typically shows intracranial dense gyriform calcifications of the affected cortical areas and/or the choroid plexus, diffuse high attenuation of the superficial and deep white matter, gyriform enhancement, brain atrophy and thickening of the calvarium (Fig. 10.8A). Contrast-enhancing leptomeningeal angioma on T1-weighted MRI is the hallmark of intracranial involvement of SWS (Fig. 10.9A). In addition, MRI can demonstrate cortical atrophy, choroid plexus enlargement (Fig. 10.9A), prominence of the deep venous system, and angiomas of the eyes. Susceptibility weighted imaging (SWI), an MRI technique with an exquisite sensitivity for defining the venous vasculature by detecting deoxygenated blood in small veins without contrast administration, has superior sensitivity to conventional T1-weighted gadolinium-enhanced MRI by showing fine details of deep transmedullary and periventricular veins (Hu et al. 2008; Juhász et al. 2007a); SWI can also visualize calcified regions, which may be difficult to appreciate on conventional MRI (Fig. 10.8B).

Functional neuroimaging with FDG PET has been used to aid in the early diagnosis (Reid et al. 1997) and (p.163)

                   Positron Emission Tomography: Brain Glucose Metabolism in Pediatric Epilepsy Syndromes

Figure 10.8 CT (A) and MRI (susceptibility weighted imaging [SWI]) (B) of a 3-month-old infant with Sturge-Weber syndrome affecting the right hemisphere. This child had daily seizures starting from the newborn period. Both scans showed severe right hemispheric atrophy with gyriform calcifications on the right side. The child underwent right hemispherectomy and became seizure-free.

assessment of the progression of the disease (Chugani et al. 1989; Juhász et al., 2007b; Lee et al. 2001). FDG PET in SWS often shows widespread unilateral hypometabolism ipsilateral to the facial nevus, and the abnormalities typically extend beyond the structural abnormalities depicted on MRI (Chugani et al., 1989; Juhász et al., 2007a; Lee et al., 2001) (Fig. 10.9B). Interestingly, children with unilateral SWS and early, rapid hemispheric progression, leading to early severe hemispheric hypometabolism, may paradoxically maintain or develop good cognitive functions (Behen et al., 2006; Lee et al., 2001). This observation suggests that functional reorganization occurs more readily when unilateral cortex is severely damaged at an early age. It is very likely that rapid demise of the affected areas, especially at younger ages, can facilitate more effective reorganization. FDG PET studies indeed demonstrated increased metabolism, likely indicating functional reorganization, in the contralateral occipital cortex of children with SWS and severe ipsilateral occipital damage (Batista et al. 2007). In contrast, cortex with mild cortical hypometabolism, which does not progress rapidly, may exert a prolonged nociferous effect on the remainder of the brain.

By studying the longitudinal changes in two consecutive glucose PET scans in 14 children with SWS and unilateral leptomeningeal angiomatosis, and correlating these changes with age, clinical seizure frequency, and hemiparesis, Juhász et al. (2007b) demonstrated that major metabolic progression in SWS occurs prior to 4 years of age, coinciding with a sharp increase of metabolic demand in the developing brain (Chugani et al. 1987). Progressive expansion of glucose hypometabolism correlated with high seizure frequency in these children. On the other hand, metabolic abnormalities may remain limited or may even recover to some extent in children with well-controlled seizures. The extent of cortical hypometabolism also correlated with an increase in hemiparesis. Taken together, these findings suggest that therapeutic interventions aimed at preventing further damage in SWS should be started early, since most of the detrimental metabolic changes occur before 4 years of age. However, children with early, rapid hemispheric progression may be observed and may not need surgery if seizures become controlled and neurocognitive functions reorganize to the opposite hemisphere.

In addition to cortical hypometabolism, a subset of young children with SWS shows a peculiar pattern of interictal hypermetabolism on the side of the angioma (Chugani et al. 1989; Juhász and Chugani 2009). This pattern typically occurs in young children (less than 2 years of age), shortly before or after their first seizure(s), and is not related to ongoing seizures or interictal spikes. Follow-up PET studies showed that cortical hypermetabolism in these cases is a transient phenomenon and invariably switches to hypometabolism in older children. It has been hypothesized that interictal hypermetabolism in young children with SWS may reflect a transient increase of metabolic demand in cortex undergoing excitotoxic tissue damage; affected children often (but not always) develop intractable seizures requiring surgical resection (Juhász and Chugani 2009). (p.164)

Landau-Kleffner Syndrome and the Syndrome of Continuous Spike-and-Wave Discharges During Slow-Wave Sleep

Landau-Kleffner syndrome (LKS) (Landau 1957) or acquired epileptic aphasia is an age-related epileptic encephalopathy associated with language regression after normal development of speech; it is associated with neuropsychological impairment and paroxysmal sleep-activated epileptiform activity, particularly in the bitemporal regions. Seizures in LKS occur in 70% to 85% of cases and may co-occur, precede, or follow the onset of language regression. The syndrome typically manifests at age 3 to 7 years; however, symptoms have been described in children as young as 18 months and as old as 13 years. EEG abnormalities and epileptic seizures in LKS usually disappear in adolescence, but language disturbances tend to persist in most patients (Duran et al. 2009).

                   Positron Emission Tomography: Brain Glucose Metabolism in Pediatric Epilepsy Syndromes

Figure 10.9 T1-weighted gadolinium-enhanced axial MRI images (A) and corresponding planes of FDG PET (B) from a 2-year-old girl with Sturge-Weber syndrome affecting the left posterior region. Contrast-enhancing leptomeningeal angioma (white arrows) was confined to the left occipital and parietal regions. The choroid plexus was also enlarged on the left side (dotted arrow). However, the FDG PET showed a more widespread hypometabolism, affecting also the entire temporal lobe (black arrows).

The syndrome of continuous spike-and-wave discharges during slow-wave sleep (CSWS) or electrical status epilepticus of slow-wave sleep (ESES) is also an age-related disorder that occurs between ages 3 and 7 years, and is characterized by variable neuropsychological impairment and epilepsy with different seizure types: partial or generalized, which occur during sleep and atypical absence during wakefulness. The EEG findings consist of intense subcontinuous paroxysmal slow spike-wave complexes during interictal sleep (Patry et al. 1971; Tassinari et al. 1977). During non-REM sleep, the EEG shows continuous generalized spike-and-wave discharges occupying more than 85% of the recording (ESES). It has been proposed that (p.165) the term ESES should be reserved to describe these EEG findings alone, without reference to specific clinical symptoms (Nickels and Wirrell 2008). Compared to children with LKS, children with CSWS tend to have more global neuropsychological dysfunction and more severe epilepsy and their epileptiform EEG abnormalities tend to predominate in the fronto-temporal or fronto-central regions.

Although the ILAE classifies LKS and CSWS as two distinct syndromes, the clinical and EEG phenotypes overlap. The EEG pattern during sleep in LKS may resemble the EEG pattern described in the syndrome of CSWS, suggesting that these two syndromes may lie along the continuum of a single age-related epileptic encephalopathy.

The neurologic substrates associated with both LKS and CSWS remain poorly understood. Structural brain damage as demonstrated by CT and MRI is usually absent, but regional functional abnormalities are often recognized on glucose metabolism PET and single photon emission computed tomography (SPECT) (da Silva et al. 1997; Gaggero et al. 1995; Harbord et al. 1999; Maquet et al. 1990, 1995; O’Tuama et al. 1992; Park et al. 1994; Rintahaka et al. 1995; Sankar et al. 1990). In LKS, the pattern of brain glucose metabolism abnormalities varies but there is a unifying abnormality in the temporal lobes (Fig. 10.10). More recently, using 11C-flumazenil (FMZ) PET scans, Shiraishi et al. (2007) demonstrated diminished FMZ binding at the tip of the left temporal lobe, while FDG PET showed hypometabolism of the bilateral medial temporal regions and left superior temporal cortex in a single 8-year-old patient with LKS.

Most PET studies on CSWS have used FDG and have shown heterogeneous abnormalities: some showed focal or multifocal areas of glucose hypometabolism, whereas others showed focal or multifocal areas of glucose hypermetabolism (De Tiege et al. 2004; Luat et al. 2006; Maquet et al. 1995; Rintahaka et al. 1995) (Fig. 10.11). In the study by da Silva et al. (1997) on 17 children with LKS, FDG PET during the awake state showed bitemporal glucose hypometabolism in the majority, although some cases presented with focal or bilateral hypermetabolism. On the other hand, FDG PET taken during the sleep state in two patients with LKS and ESES showed a relative increase in glucose metabolism in the bilateral temporal cortex compared to the scans performed during the awake state (Rintahaka et al. 1995). Absolute glucose metabolic rates were not measured. The authors hypothesized that the relative increase in glucose metabolism during sleep may be an expression of functional dysregulation. In contrast, the patterns noted by Maquet et al. (1995) on six patients with CSWS were somewhat different. Five of the six showed regional increase in glucose metabolism both in the awake and sleep states. In two patients, during the sleep state, the location of the unilateral continuous spike-and-wave discharges was consistent with the area showing regional hypermetabolism. In three other patients, although the discharges were bilateral, glucose metabolism was increased in a restricted area of one hemisphere, the location of which was in close concordance with the predominant EEG abnormalities. In all of these five patients, regional glucose hypermetabolism was still observed during wakefulness, although the EEG changes were no longer continuous. The authors hypothesized that the underlying etiology of glucose hypermetabolism noted even during the awake state may be related to the disorder itself, associated with outbreak of spike-and-wave discharges, or may represent

                   Positron Emission Tomography: Brain Glucose Metabolism in Pediatric Epilepsy Syndromes

Figure 10.10 FDG PET scan of a 4-year-old girl with Landau-Kleffner syndrome showing hypometabolism of the bilateral superior temporal gyrus (arrows).

(p.166)
                   Positron Emission Tomography: Brain Glucose Metabolism in Pediatric Epilepsy Syndromes

Figure 10.11 FDG PET studies of three different patients with CSWS showing heterogenous abnormalities: some showed focal or multifocal areas of glucose hypometabolism (dotted arrows), whereas others showed focal or multifocal areas of glucose hypermetabolism (black arrows).

an increased inhibitory drive in an attempt to control the outbreak of epileptic discharges.

Recently, de Tiege et al. (2004) have identified three glucose metabolic patterns in patients whose EEGs show ESES: Group 1, presence of hypermetabolic cortical areas related to epileptic foci and associated with hypometabolic areas; Group 2, presence of one or multiple areas of hypometabolism; and Group 3, absence of significant abnormalities. The association of right parietal hypermetabolism and bifrontal hypometabolism was specific for Group 1, suggesting the presence of altered functional connectivity between the parietal and frontal cortices. The authors speculated that remote functional inhibition may be related to direct intracortical connections from the epileptic focus to the hypometabolic area or polysynaptic pathways involving subcortical structures.

The Commission on Classification and Terminology of the ILAE has categorized the syndrome of CSWS under a group of syndromes undetermined as to whether they are focal or generalized. However, as reviewed here, there are functional neuroimaging and neurophysiologic data suggesting that the generalized spike-and-wave discharges in CSWS are a result of secondary bilateral synchrony. For example, neuroimaging studies have demonstrated focal glucose hypermetabolism on FDG PET (Maquet et al., 1995; Park et al., 1994) and focal decreased (or increased) blood flow on SPECT in patients with continuous spike-and-wave during slow wave sleep (Gaggero et al. 1995). It was reported that the hypermetabolic regions identified by FDG PET correlated with the epileptic focus on EEG (De Tiege et al., 2004; Maquet et al., 1995). Our own group studied the relationships between the brain glucose metabolism patterns and objectively defined EEG parameters in six children with CSWS (Luat et al. 2005). In five of the six patients, areas of increased glucose metabolism were noted to be either confined to one hemisphere or were highly asymmetric. The origin of the spike-and-wave activity determined by sequential voltage mapping was generally concordant with the brain regions showing increased glucose metabolism. One patient underwent surgical resection of the hypermetabolic region, which was the same area noted to be the origin of generalized spike-and-wave discharges. This child became seizure-free and improved cognitively, suggesting that in at least some subjects with CSWS, resective surgery may be beneficial, provided that there is concordance between the location of focal hypermetabolism and localization of ESES based on sequential voltage mapping.

Lennox-Gastaut Syndrome

Lennox-Gastaut syndrome (LGS) is an epilepsy syndrome characterized by multiple seizure types, including brief tonic, atonic, myoclonic, and atypical absence seizures, associated with intellectual disability and an interictal EEG pattern of diffuse, slow (less than 2.5 Hz) spike-wave complexes. In sleep, bursts of fast rhythmic waves and slow polyspikes, and generalized fast rhythms at about 10 Hz are also seen (Beaumanoir and Blume 2005). Several studies have demonstrated the interictal PET scan patterns in children with LGS (Chugani et al. 1987; Ferrie et al. 1996; Gur et al. 1982; Iinuma et al. 1987, Miyauchi et al. 1988, Theodore et al. 1987). Most cases demonstrated bilateral diffuse glucose hypometabolism (Fig. 10.12). However, there were cases showing focal or unilateral diffuse abnormalities. For example, Gur et al. (1982) reported two (p.167)

                   Positron Emission Tomography: Brain Glucose Metabolism in Pediatric Epilepsy Syndromes

Figure 10.12 FDG PET scan of a 13-year-old girl with Lennox-Gastaut syndrome demonstrating bilateral glucose hypometabolism. EEG during the PET scan showed generalized slow spike-and-wave discharges consistent with Lennox-Gastaut syndrome.

adult patients with LGS who underwent FDG PET study before and after corpus callosotomy. Both preoperative scans showed left temporal hypometabolism compared to the contralateral side. Six weeks postoperatively, repeat FDG PET on the patient who had persistent seizure showed persistence of the left temporal lobe glucose hypometabolism. However, repeat FDG PET of the second patient, whose seizures became controlled after callosotomy, revealed a higher metabolic rate in the previously noted hypometabolic temporal lobe. These findings suggest that a temporal lobe seizure focus could be present in some patients with LGS. Theodore et al. (1987), on the other hand, did not find any focal abnormalities in their study of five children with LGS. Chugani et al. (1987), who studied a larger number of patients (n = 15), identified four metabolic subtypes: unilateral focal, unilateral diffuse, bilateral diffuse hypometabolism, and normal patterns; the most common pattern was bilateral diffuse hypometabolism. They also demonstrated that the focal areas of glucose hypometabolism need not be confined to the temporal lobe but can also be seen in the frontal regions. The finding of focal glucose hypometabolism (whether unilateral diffuse or unilateral focal) implies that surgical resection of these focal areas, if proven by intensive EEG monitoring to be the origin of a substantial number of seizures, may be an alternative treatment option for patients with LGS.

Rasmussen Encephalitis

Rasmussen encephalitis (Rasmussen 1958) is a rare form of chronic focal encephalitis characterized by intractable focal seizures, hemiplegia, and progressive encephalopathy, associated with inflammation and progressive atrophy of a single hemisphere. The pathogenesis of Rasmussen encephalitis is believed to be immune-mediated, involving both humoral autoimmunity and T-cell–mediated cytotoxicity. Autoantibodies to glutamate receptor GluR3 in Rasmussen encephalitis have been implicated in the pathogenesis of this disorder by some investigators (McNamara et al. 1999; Rogers et al. 1994).

Due to the progressive neurologic deterioration that accompanies Rasmussen encephalitis, aggressive treatment is necessary and surgical hemispherectomy is the mainstay of treatment. Thus, early diagnosis is necessary. Progressive, lateralized cerebral hemiatrophy demonstrated by CT and MRI is the characteristic finding in Rasmussen encephalitis. However, during the early stages of the disease, structural imaging may be normal. In this situation, functional neuroimaging using SPECT or PET scanning can detect functional abnormalities (Burke et al. 1992; Kaiboriboon et al. 2000; Lee et al. 2001).

Typically, glucose metabolism PET scanning in children with Rasmussen encephalitis shows unilateral lobar or hemispheric hypometabolism, but within the hypometabolic zone, focal areas of hypermetabolism may be found that represent sites of epileptic activity (Fig. 10.13). Lee et al. (2001) has demonstrated the order of progression of the cerebral glucose metabolism abnormalities during the early and late stages in 15 children with biopsy-proven Rasmussen encephalitis. During the early stages (less than 1 year from seizure onset), abnormal glucose metabolism is typically seen in the frontal and temporal regions and less frequently in parietal areas, whereas the posterior cortex is preserved. In the later stages of the disease (more than 1 year after onset of seizures), FDG PET studies show more extensive hemispheric involvement, including the occipital cortex, but the functional (p.168)

                   Positron Emission Tomography: Brain Glucose Metabolism in Pediatric Epilepsy Syndromes

Figure 10.13 A 9-year-old boy with Rasmussen encephalitis who presented with intractable focal motor seizure involving the left body. The FDG PET brain images showed increased glucose metabolism in the right central region, right thalamus, and left cerebellum related to ongoing seizure activity and propagation.

abnormalities remained lateralized. The authors suggested that identification of the most involved areas by PET even during the early stages when MRI is usually normal may serve to guide the site of brain biopsy and may therefore facilitate the diagnosis and early treatment of the disease.

Hemimegalencephaly

Hemimegalencephaly is a rare developmental brain malformation characterized by unilateral hemispheric enlargement and ventriculomegaly, arising from abnormalities of neuroglial differentiation and cellular migration involving predominantly one hemisphere. Some investigators believe that hemimegalencephaly results from neuronal migration disturbances between the third and fifth months of gestation, while others believe that it is a primary disorder of cellular lineage, differentiation, and proliferation (Flores-Sarnat 2002) (see also Chapter 3).

Hemimegalencephaly may occur in isolation as a sporadic disorder (without associated hemicorporal hypertrophy or cutaneous or systemic manifestation) or as part of a neurocutaneous syndrome, such as neurofibromatosis, epidermal nevus syndrome, linear nevus sebaceous syndrome, hypomelanosis of Ito, and Klippel-Trenaunay-Weber syndrome. The clinical features of hemimegalencephaly include epilepsy, mental retardation, and hemiparesis.

Epilepsy in hemimegalencephaly often becomes drug-resistant, and cerebral hemispherectomy is the recommended treatment option. The MRI demonstrates cerebral hemisphere hypertrophy, with enlargement of the lateral ventricle, an abnormal gyral pattern with a thick cortex, and gliosis in the white matter of the affected side (Fig. 10.14A) (Barkovich and Chuang 1990). Advanced myelination in the affected hemisphere has been reported. Interictal glucose metabolism PET typically shows hypometabolism in the involved hemisphere (Fig. 10.14B) but may also show intense hypermetabolism associated with continuous seizure activity such that interictal PET scans are difficult to acquire (Rintahaka et al. 1993). In addition, FDG PET may reveal that the apparently normal hemisphere, based on MRI, may in fact not be entirely normal because of focal areas of hypometabolism, suggesting the presence of additional underlying structural abnormalities at the microscopic level. This observation may explain why even after hemispherectomy, children with hemimegalencephaly, as a group, have a relatively poorer developmental outcome compared to children who underwent hemispherectomy for other disorders, such as SWS or Rasmussen encephalitis. Preoperative assessment of the contralateral hemisphere using glucose metabolism PET scanning is therefore useful to assess its integrity, thereby providing important prognostic information (Rintahaka et al. 1993).

Severe Myoclonic Epilepsy of Infancy (Dravet Syndrome) and Generalized Epilepsy with Febrile Seizure Plus

Severe myoclonic epilepsy of infancy or Dravet syndrome (Dravet 1978) is an intractable epilepsy syndrome initially presenting with fever-induced prolonged, generalized or unilateral clonic seizures followed by the development of mixed seizure types: generalized tonic-clonic, myoclonic, atypical absence, (p.169)

                   Positron Emission Tomography: Brain Glucose Metabolism in Pediatric Epilepsy Syndromes

Figure 10.14 (A) T1-weighted MRI of a 2-year-old boy with intractable left-sided focal motor seizures and hemimegalencephaly showing right cerebral hemisphere hypertrophy, with enlargement of the right lateral ventricle and an abnormal gyral pattern with a thick cortex, and gliosis in the white matter of the affected hemisphere. (B) FDG PET of the same child showing glucose hypometabolism in the involved hemisphere and normal glucose metabolism in the contralateral side.

and focal seizures with or without secondary generalization. Other neurologic features include progressive psychomotor delay and ataxia. Generalized epilepsy with febrile seizure plus (GEFS+) is a childhood-onset epilepsy syndrome of multiple febrile seizures, but unlike the typical febrile convulsion syndrome, attacks with fever continue beyond 6 years of age, or afebrile seizures occur (Scheffer and Berkovic 1997). Both conditions can arise from mutations of the SCN1A gene, the gene encoding the alpha 1 pore-forming subunit of the sodium channel (Claes et al. 2001; Escayg et al. 2000). The majority of patients with Dravet syndrome and GEFS+ have mutations of SCN1A. In addition, GEFS+ is associated with mutation of the beta subunit of the sodium channel, SCN1B (Wallace et al. 1998) and the GABAA receptor gamma 2 subunit, GABARG2 (Baulac et al. 2001).

Structural neuroimaging is usually nonspecific and does not demonstrate brain lesions. Glucose metabolism PET studies of these children have shown diffuse, bilateral cortical glucose hypometabolism with relative preservation of the basal ganglia (Fig. 10.15). Although some children may show subtle asymmetries in cortical glucose metabolism, the overall pattern is a diffuse, bilateral cortical glucose hypometabolism. Since focal seizures may occur in this condition, genetic testing, if positive, should preclude epilepsy surgery.

Glucose Metabolism PET Studies in Children on Ketogenic Diet

The ketogenic diet is a high-fat, low-protein, and low-carbohydrate diet that has been used for the treatment of intractable epilepsy. It has been used for various pediatric epilepsy syndromes, including infantile spasms, myoclonic-astatic epilepsy, severe myoclonic epilepsy syndrome of infancy or Dravet syndrome, LGS, TSC, LKS, and glucose transporter protein 1 deficiency (Kosoff et al. 2009).

The mechanism of action of the antiepileptic effects of the ketogenic diet is still controversial, but several mechanisms have been proposed (Bough and Rho 2007). The hallmark feature of ketogenic diet therapy is the achievement of ketosis as a consequence of increased fatty acid oxidation. It has been speculated that ketosis modifies the tricarboxcylic acid cycle to increase brain gamma aminobutyric acid (GABA) synthesis. The ketogenic diet increases the production of polyunsaturated fatty acids, which in turn induce the expression of neuronal uncoupling proteins, causing upregulation of numerous energy metabolism genes, and mitochondrial biogenesis. Others have hypothesized that glucose restriction during the ketogenic diet activates adenosine triphosphate (ATP)-sensitive potassium channels that lead to membrane hyperpolarization. Overall, these changes stabilize synaptic function and increase the resistance to seizure generation.

Since many patients with intractable epilepsy on the ketogenic diet are also referred for PET scanning as part of epilepsy surgery evaluation, it is important to note the effect of the diet on brain glucose metabolism. During starvation and the ketotic state, brain energy metabolism in humans shifts towards oxidation of ketone bodies. Changes in glucose availability during starvation and administration of the ketogenic diet provide the earliest evidence of cerebral metabolic (p.170)

                   Positron Emission Tomography: Brain Glucose Metabolism in Pediatric Epilepsy Syndromes

Figure 10.15 FDG PET scan of a 4-year-old boy with generalized epilepsy with febrile seizure plus (GEFS+) and SCN1A gene mutation showing severe bilateral cortical hypometabolism with relative sparing of the primary visual cortex. Prominence of the spared bilateral basal ganglia is noted.

adaptation (Prins 2008). During starvation and administration of the ketogenic diet, plasma glucose diminishes and the availability of plasma ketones increases, as does its transport to the brain. Melo et al. (2006) have shown a decrease in neuronal oxidative metabolism of glucose and an increase in astrocytic oxidative metabolism of acetate in starved rats. During short-term starvation in humans, the presence of ketones decreases brain glucose consumption in the cortex and in the cerebellum (Hasselbach et al. 1994). Using Patlak analysis, it has been demonstrated that the cerebral metabolic rate of glucose consumption in the cortex and cerebellum of ketotic rats is reduced by 10% per mM of plasma ketone bodies (LaManna et al. 2009). Taken together, these observations imply that children on the ketogenic diet will have an expected decrease in global cerebral glucose metabolism. Hence, FDG PET scanning for seizure focus localization while these patients are on the ketogenic diet is not ideal. The few such studies that have been performed have been difficult to interpret. Therefore, our policy has been not to perform FDG PET studies while patients are on the ketogenic diet.

Conclusion

We have discussed the value and clinical utility of glucose metabolism PET scanning in various pediatric epilepsy syndromes. As part of the presurgical evaluation for intractable epilepsy in children, FDG PET has an established role not only in the lateralization and localization of the epileptic focus, especially if structural imaging is normal, but also in the assessment of the functional integrity of areas outside the epileptic zone. FDG PET has provided important insights regarding the pathogenesis and mechanisms of different epilepsy syndromes, particularly cryptogenic epileptic spasms, resulting in altered treatment approaches in these children. In certain other catastrophic epilepsy syndromes like Rasmussen encephalitis, it has provided us with a means of early diagnosis that leads to prompt intervention.

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