The present study demonstrates that focal cortical increase of interictal glucose metabolism is a relatively common phenomenon in young children with SWS. In our cohort, 28% of patients younger than 2 years of age showed this seemingly paradoxical pattern of metabolism. The close relationship between the onset of first seizure and the occurrence of cortical hypermetabolism suggests that this metabolic phenomenon may be associated with processes related to epileptogenesis. Interestingly, hypermetabolism was always transient and its localization appears to be age-dependent: posterior cortex, the most common site of the primary pathology, was involved early (in younger patients), whereas pure frontal hypermetabolism, associated with posterior hypometabolism, was seen at older ages. From a clinical point of view, high rate of intractable epilepsy requiring epilepsy surgery in children with increased metabolism is perhaps the most interesting finding; this suggests that FDG-PET hypermetabolism may be an imaging marker of drug-resistant seizures in SWS.
Glucose hypermetabolism in SWS
The phenomenon of increased cortical glucose metabolism in SWS along with the typical hypometabolic pattern in advanced stages of SWS was initially demonstrated by Chugani et al. (1989). In that study, interictal glucose hypermetabolism was seen in three patients of the whole series of 12 cases. A subsequent multimodality imaging study also reported two infants with glucose hypermetabolism (Pfund et al., 2003). Similarly, interictal hyperperfusion of the affected brain region was seen on SPECT studies in infants before epilepsy onset but not in older children (Pinton et al., 1997). Interictal hypermetabolism and hyperperfusion appear to be transient phenomena, since available follow-up SPECT and PET scans (including those in the present study) invariably demonstrated an interval switch to decreased perfusion and metabolism, respectively. By studying a relatively large series of patients with this rare disorder, we have now provided further details about the prevalence, localization, and longitudinal course of cortical hypermetabolism.
Interestingly, the most common location of glucose hypermetabolism in our patients was the frontal lobe. Indeed, increased glucose metabolism was solely localized to the frontal lobe in older patients, with concomitant posterior hypometabolism, whereas in younger children (infants) increased glucose uptake was seen in posterior cortical areas as well. The exact evolution and regression process of cortical hypermetabolism is unknown. Because the majority of PET scans showed no signs of increased metabolism even in young children with SWS, it is likely that affected patients represent a distinct subgroup, although the true prevalence of this metabolic phenomenon is probably higher, as some patients may have undergone a transient hypermetabolic state before their first PET scan. It is also conceivable that a substantial portion of the affected cortex shows a transient increase in metabolic demand some time during the very early course of the disease, and then this switches to hypometabolism, as the cortical injury expands from posterior angioma–affected regions to structurally less-affected frontal areas.
Glucose hypermetabolism and epilepsy
Increased metabolic activity in the region of the seizure focus, as a consequence of excessive neuronal firing and increased energy consumption, is commonly seen during seizures or even in the presence of persistent focal interictal epileptiform activity in patients with epilepsy (Engel et al., 1982; Bittar et al., 1999). In the present study, however, the PET scans of all nine patients showing cortical hypermetabolism were acquired in the interictal state at least days after a clinical seizure and without the concomitant presence of epileptiform discharges on scalp EEG performed during the PET scan (see Table 1). Therefore, it can be argued that the pathomechanism of the detected focal hypermetabolism in SWS may not be associated directly with epilepsy, or with ongoing epileptiform activity. However, our data show that this transient phenomenon occurs mostly in young (mainly younger than 2 years of age) patients during a limited period before and shortly after the first clinical seizures. Transient interictal glucose hypermetabolism seems to be a unique feature of SWS associated with epilepsy, given the fact that partial epilepsy is commonly associated with focal glucose hypometabolism (in the interictal state). Furthermore, hypometabolism is relatively rare (and hypermetabolism has not been reported) in new-onset (nonlesional) partial epilepsy (Kuhl et al., 1980; Gaillard et al., 2002). Similarly, transient hypometabolism, but not hypermetabolism, has been reported in children with recent-onset West syndrome (Maeda et al., 1994; Natsume et al., 1996).
Mechanism of increased glucose metabolism: implications for epileptogenesis
Interictal glucose hypermetabolism has been reported rarely in neurologic conditions other than SWS. In the nickel-induced epilepsy model of rats, the intracortical pattern of glucose hypermetabolism and the presence of hypermetabolism in the absence of seizures indicated that not only the seizure activity itself, but also excitotoxic tissue damage may play a key role in increased glucose metabolism (Cooper et al., 2001). A recent report of two siblings with West syndrome demonstrated the atypical finding of focal glucose hypermetabolism in the interictal state (Kumada et al., 2006). Paradoxical increase in focal cortical glucose metabolism has also been reported in a few epileptic patients with malformations of cortical development (Poduri et al., 2007). Interestingly, cortical malformations have been identified recently in patients with SWS, and intractable epilepsy and may be the primary cause of epilepsy, at least in some cases, although no direct evidence has been provided for this notion (Maton et al., 2010). In addition, transient glucose hypermetabolism in bilateral basal ganglia has been reported in a newborn with hypoxic–ischemic encephalopathy and developed epilepsy as well as dystonic cerebral palsy (Batista et al., 2007). Based on earlier magnetic resonance spectroscopy findings showing increased glutamate concentration in the basal ganglia following perinatal hypoxia, it has been also suggested that the transient increase in glucose metabolism may be associated with hypoxia-induced excessive glutamatergic activity, a major source of excitotoxicity.
It has been shown that a significant proportion of energy metabolism of the brain is utilized for glutamatergic synaptic activity (Sibson et al., 1998). Imbalance in ionic homeostasis as well as excitotoxicity plays a crucial role also in posttraumatic cerebral glucose hypermetabolism (Bergsneider et al., 1997). Furthermore, perinatal hypoxia can lead to excessive stimulation of glutamate receptors along with the downregulation of γ-aminobutyric acid (GABA) receptor and glutamate decarboxylase genes; decreased levels of components of the GABA pathway play an important role in cell injury and may lead to high susceptibility to seizures (Johnston, 2005; Anju et al., 2010). An earlier study also showed increased regional glucose metabolism in five of six infants with hypoxic–ischemic encephalopathy, and suggested that detection of early cerebral hypermetabolism may have clinical predictive value (Blennow et al., 1995). Indirect evidence supports the notion that hypoxia-induced excitotoxicity can be the underlying mechanism of initial hypermetabolism and hyperperfusion in infants with hypoxic-ischemic encephalopathy (Hagberg et al., 1993). Because a tight coupling between glucose metabolism and glutamate cycling has been demonstrated in patients with partial epilepsy (Pfund et al., 2000), ischemic injury of the cortex in SWS may lead to glutamate excitotoxicity in conjunction with glucose hypermetabolism. In addition, the appearance of glucose hypermetabolism in young ages, within close temporal proximity to the first clinical seizures, suggests that the underlying excitotoxic damage ultimately may reach a critical level to trigger seizures. Although somewhat speculative, transient focal hypermetabolism may be also related to enhancement of GABAergic synaptic transmission that could transitorily compensate for the ongoing glutamate-mediated injury (Liang et al., 2009), imposing further metabolic demand to the affected brain region. Failed compensation may eventually result in excessive excitotoxic damage and seizure generation.
A recent study on cortical tissue samples obtained from infants with SWS and epilepsy (Tyzio et al., 2009) provides support that the above-detailed mechanisms may indeed play a role in SWS-related epileptogenesis. In that study, cortical neurons were found to be depolarized and displayed synchronous activity driven by glutamatergic connections. This pattern was more consistent with ischemic damage than injury resulting from the epileptogenic process itself. Interestingly, the authors also found that, despite the young age of the patients, GABA exerted an inhibitory and anticonvulsive role via a shunting mechanism in SWS cortex; this was clearly different from the excitatory GABA action described in human epileptic cortex of other etiology (such as cortical dysplasia) (Cepeda et al., 2007). Altogether, these results suggested the presence of an SWS-specific epileptogenic process (perhaps due its unique, chronic ischemia-induced cortical damage), which may explain why early metabolic patterns are different in some children with SWS as compared to other pediatric epilepsy syndromes.
The presence of glucose hypermetabolism even shortly after the first clinical seizure(s) in children with SWS is not surprising, since epileptogenesis is a dynamic process extending well beyond the onset of the first seizure (Williams et al., 2009), and progressive, age-dependent metabolic changes (hyper- as well as hypometabolism) occur in the brain of rats during epileptogenesis (Dube et al., 2000, 2001; Guo et al., 2009). Interestingly, chronic inflammation, angiogenesis, and blood–brain barrier leakage (the latter two are also present in SWS), as potential mechanisms of epileptogenesis, appeared to be age-dependent in a rodent model (Marcon et al., 2009). Increased glucose metabolism (measured by autoradiography) was found also in nondamaged brain regions of rats after induced status epilepticus, possibly indicating processes working against or controlling seizure activity (Dube et al., 2000). Combined in vivo measurements of substrates of the glutamate and GABA pathways and glucose utilization (MR-spectroscopy/FDG-PET) in infants with SWS could shed more light on the underlying mechanisms of cortical hypermetabolism.
Finally, our data suggest that epilepsy surgery due to uncontrolled seizures tend to be more frequent in patients whose FDG-PET scan showed interictal hypermetabolism than in those whose early scan did not detect hypermetabolism. If further, prospective studies confirm this observation, early PET scanning in SWS using the tracer FDG could have a crucial clinical value in identifying children with higher risk for intractable seizures.