¹⁸F-fluorodeoxyglucose and ¹⁸F-flumazenil positron emission tomography in patients with refractory epilepsy

Epilepsy is a neurological disorder characterized by epileptic seizures as a result of excessive neuronal activity in the brain (the word “epilepsy” is derived from the Greek word meaning to be attacked or seized). For diagnosis of epilepsy at least two unprovoked seizures are required. Metabolic, genetic or structural conditions can be recognized as causes of epilepsy, but in 60% of patients, the cause remains unknown.¹ Approximately 65 million people worldwide suffer from epilepsy², 20–40% of them are refractory to medication therapy.³ Depending on the epilepsy syndrome, dietary changes, neurostimulation or surgery may be considered as treatment options in patients whose seizures do not respond to medication therapy. With the advancement of surgical techniques and devices, surgical treatment has become the treatment of choice in patients who are unresponsive to medication therapy. In selected patients with focal structural lesions such as cortical dysplasia, mesial temporal sclerosis, vascular malformations and in some paediatric epilepsy syndromes, surgery may substantially reduce the frequency of epileptic seizures and improve the patient´s quality of life. Several studies over the last decades support the statement that surgical treatment significantly improved long-term outcomes of seizure control.⁴-⁸

Early detection of disease is crucial in the management of patients with epilepsy. Correct localization of the ictal onset zone is associated with a better surgical outcome. Epilepsy surgery may lead to seizure freedom. When “surgical cure” is impossible, epilepsy surgery may help achieve palliative goals such as minimizing the frequency and severity of seizures. Following successful epilepsy surgery, quality of life, cognition and behaviour may improve substantially.⁹ However, careful patient selection and weighing of risks and benefits are of paramount importance, as surgery may not only fail in terms of improving seizure control, but come with serious adverse events such as intracranial bleeding. Despite international guidelines recommending early and systematic assessment of patient´s eligibility, epilepsy surgery is still being underused and referral of patients with drug refractory epilepsy is often delayed with deleterious consequences on outcome and quality of life.¹⁰

The scope of this paper on PET imaging in refractory epilepsy patients cannot cover all aspects of patient management including the range of indications, specific issues in children and adults, surgical techniques or predictors of outcome. For this, the interested reader is referred to a recent review of Ryvlin et al.¹¹

Non-invasive focus localisation of seizures precedes invasive intracranial electrodes procedures. The modern non-invasive techniques used for structural-functional localization of the seizure focus includes electroencephalography (EEG) monitoring, magnetic resonance imaging (MRI), single photon emission tomography/computed tomography (SPECT/CT) and positron emission tomography/computed tomography (PET/CT).

EEG has low sensitivity in the diagnosis of seizure disorders (25–56%).

MRI is a sensitive and specific imaging modality for identifying hippocampal sclerosis as well as other lesions responsible for epilepsy. However 1–1.5 T MRI still fails to reveal approximately 20% of abnormalities in patients with medically refractory epilepsy¹²; MRI may miss mild changes and subtle lesions. In patients with intractable extratemporal epilepsy, the most common underlying pathology is microscopic cortical dysplasia which sometimes cannot be detected by MRI and hence may pass unnoticed by ¹⁸F-FDG PET/CT as well. A recent study of 194 adult patients with medically refractory focal epilepsy showed that ¹⁸F-FDG PET/CT is helpful for decision making in 53% of presurgical patients with normal or discordant MRI.¹³ Advanced MRI technologies (MR spectroscopy, MR volumetry, MR perfusion) may provide additional and more precise information.

In recent years brain perfusion SPECT imaging has been widely used for detection of epileptic focus. In their meta-analysis, Devous et al. reported a 44% (interictal), 75% (postictal) and 97% (ictal) sensitivity of SPECT in patients with temporal lobe epilepsy.¹⁴ Extratemporal lobe epilepsy showed SPECT sensitivity in 66% (ictal) and in 40% (interictal) of patients.¹⁵,¹⁶

In recent years, multiple studies¹⁷-²² have demonstrated that ¹⁸F-FDG PET/CT can predict surgical outcome in patients with refractory epilepsy. Actually ¹⁸F-FDG PET/CT has proven to be the most sensitive imaging technique for presurgical localization of epileptogenic foci in patients with medically refractory partial epilepsy who have non-contributory MRI and EEG. In comparison to SPECT, PET technology provides much better resolution and allows quantitative measurement.²³-²⁶

There is a variety of PET tracers used for imaging of epileptic focus: tracers that measure glucose metabolism, serotonine receptors and transport, oxygen metabolism, cerebral blood flow and other receptor binding.²⁷ PET scan findings at the area of a seizure focus are different according to the PET tracer used (Table 1). Multiple PET radiotracers for neurotransmitter and neuromodulator systems still form part of preclinical trials.

In this review article we focus on the routinely used tracer ¹⁸F-FDG as well as on ¹⁸F-labelled flumazenil tracers which are less available but becoming popular.

The first application of ¹⁸F-FDG PET/CT in patients with epilepsy dates back to the early 1980s.²⁸,²⁹ As glucose is the main energy source for the brain, a radioactive glucose analogue has been the most widely used tracer for PET imaging in patients with refractory epilepsy. There is a good match of glucose metabolism and neuronal activity. Glucose transporters (predominantly GLUT1) transfer ¹⁸F-FDG from the blood into cells. Once in the cell, FDG is phosphorylated by hexokinase and forms FDG-6-phosphate. Further metabolism of FDG-6-phosphate is stopped and FDG-6-phosphate is essentially trapped in the cell.

In 2009 the European Association of Nuclear Medicine established an imaging protocol for ¹⁸F-FDG PET/CT imaging of the brain.³⁰ According to this protocol patients should fast at least 4 hours before scanning. Psychotropic pharmaceuticals may influence reagional metabolism of the glucose. Serum glucose levels must be checked before ¹⁸F-FDG PET/CT examination. If the value is greater than 160 mg/dl, the patient must be rescheduled. Diabetic patients should undergo scanning in euglycemic state. At least 30 minutes before examination as well as 30 minutes after tracer injection patients must rest in a quiet dimly-lighted room. They should be instructed not to talk, read or to be otherwise active. ¹⁸F-FDG dose for adults patients is 300–600 MBq in 2-D mode and 125–250 MBq in 3-D mode. For children, dose is calculated by body wight (EANM dosage card). Continuous EEG recording is required 2 hours before tracer injection (to exclude that tracer is not injected postictal state) and at least until 20 minutes after tracer injection. Static PET scan acquisition starts 30 up to 60 minutes after tracer injection and lasts for 15–30 minutes. There are small variations in the protocols depending on quality of imaging technology. In PET scans interpretation, combination of visual inspection and semiquantitive analysis is crucial. Semiquantitative analysis helps to detect abnormalities which are not present on visual inspection.

Physiological¹⁸F-FDG distribution is as follows: high in cerebral and cerebellar cortices and subcortical grey matter and mild in the white matter. In children and with normal aging there is decrease in cerebral metabolic rates (particularly in lateral, medial frontal cortex and anterior cingulate cortex).³¹,³² Regions involving epileptic foci may present increased, reduced, or, absent metabolic activity.

¹⁸F-FDG PET/CT scans in patients with epilepsy are usually obtained in the interictal phase. Ictal ¹⁸F-FDG PET/CT appears to be highly sensitive (Figure 1), but is difficult to obtain because of unpredictability and very rapid onset of major seizures. In addition, medical personnel and the radiotracer must be available at the patient´s bedside at the time of seizure onset. Postictal ¹⁸F-FDG PET/ CT scans can be very complex, and it represents a mishmash of increased and/or decreased metabolism, depending on the time of ¹⁸F-FDG injection after the onset of seizure.

Figure 1

The goal of implementing ¹⁸F-FDG PET/CT in the management of patients with drug refractory epilepsy was to obtain functional imaging of interictal brain glucose metabolism. Multiple studies have shown that interictal ¹⁸F-FDG PET/CT is more sensitive than interictal perfusion SPECT³³-³⁴,¹⁵, because in the interictal period, reduction of regional glucose cerebral metabolism is more pronounced than reduction of cerebral perfusion.³⁵-³⁷

Neuronal loss due to chronic seizure activity, reduction in density of synapses, inhibitory processes in the interictal period and diaschisis also influence glucose hypometabolism, the characteristic sign of epilepsy on interictal ¹⁸F-FDG PET/ CT. Interictal ¹⁸F-FDG PET/CT cannot precisely define the surgical margins, because some areas of hypometabolism extend beyond epileptic zones. Drzezga et al. showed that automated analysis of ¹⁸F-FDG PET/CT scans in patients with epilepsy is more sensitive than visual analysis in patients with temporal lobe epilepsy and extra temporal lobe epilepsy.³⁶ The combination of MRI and interictal ¹⁸F-FDG PET/CT will probably evolve as the future modality of choice to get the best results for presurgical evaluation.

Ictal ¹⁸F-FDG PET in the presurgical workup of refractory epilepsy is rarely performed; it is performed either in status epilepticus or in a status of induced epileptic seizures. As status epilepticus is defined as seizure longer than 30 minutes or more than one seizure within thirty minutes without the person returning to normal, ¹⁸F-FDG PET is difficult to be obtained in those moments. Despite technical difficulties ictal ¹⁸F-FDG PET has the advantage of a high spatial resolution. Ictal ¹⁸F-FDG PET/CT shows hypermetabolism, although an ictal scan reveals a complex combination of hyper and hypometabolism and for that reason it is important to continuously monitor the patient with scalp EEG. A study from 2013 showed that in patients with incompatible EEG, MRI and clinical features, ictal ¹⁸F-FDG PET/CT helped to localize the origin of status epilepticus.³⁸ Definition of an ictal onset zone is usually made visually with the support of semiquantitative analysis. A difference above 15% between the affected and the contralateral side suggests significant physiological asymmetry.

Unfortunately, ¹⁸F-FDG is not an ideal PET tracer regarding the management of patients with epilepsy. Areas of glucose hypometabolism do not correlate with the proven degree of change within hippocampal sclerosis, as observed by histopathology or MRI; the area of hypometabolism may be larger than the pathological seizure focus.³⁹ So, the presurgical definition of epileptogenic foci cannot be based on ¹⁸F-FDG PET/CT imaging alone, because ¹⁸F-FDG changes may appear larger than the real ictal onset zone. The reason for this anatomical-functional discrepancy has not been explained yet. However, ¹⁸F-FDG PET/CT can reveal and confirm surgical targets and therefore represents a valuable tool in the management of patients with intractable epilepsy.

Gamma-aminobutyric acid (GABA) is the most important inhibitory neurotransmitter in the central nervous system.⁴⁰-⁴³ Its main role consists of reducing neuronal excitability and regulating muscle tone. There are two types of GABA receptors: GABA_A and GABA_B; benzodiazepine receptors are modulatory sites on GABA_A receptors. Benzodiazepine distribution in the human brain includes the occipital cortex, temporal cortex, cerebellum, thalamus, and the pons. The majority of GABA_A receptors are benzodiazepine-sensitive, but there are also GABA_A receptors which are insensitive to classical benzodiazepines. Benzodiazepines enhance the action of GABA on its receptors, thus having anticonvulsant, sedative, hypnotic, anxiolytic and muscle-relaxant effects.

Flumazenil blocks the benzodiazepine sites on GABA_A receptors and thus antagonizes the action benzodiazepines have on the central nervous system. Flumazenil was introduced in 1987 and over time it was used as an antidote for the treatment of benzodiazepine overdoses. In epileptogenic regions a reduced level of benzodiazepine receptors is found⁴⁴; also, irreversible ischemic cortical damage after stroke⁴⁵, Alzheimer disease⁴⁶,⁴⁷ chronic alcoholism⁴⁸ and schizophrenia⁴⁹ may influence benzodiazepine complex density.

In the 1980s, Flumazenil was proposed as a promising new marker for imaging of benzodiazepine receptors by PET. The substance was initially labelled with Carbon-11 (¹¹C-FMZ)⁵⁰ and used in some studies: the majority of patients with seizures refractory to medical treatment had hippocampal sclerosis characterized by neuronal loss and gliosis, which was detected by this positron-labelled GABA_A receptor antagonist.⁵¹ Six years later a SPECT agent, ¹²³I-iomazenil, was synthetized.⁵²,⁵³ Both compounds showed high benzodiazepine binding potential in the brain. However, use of ¹¹C-FMZ in clinical practice has been limited by its short half-life, necessitating an on-site cyclotron for production, and multiple syntheses if several subjects have to be examined. The first paper on a fluorinated analogue of flumazenil was published in 1992.⁵⁴¹⁸F-labelled PET radiotracers are more suited for clinical use. Also, the shorter positron range of ¹⁸F provides better image resolution, which may enhance the detection of small pathological complexes such as epileptic foci. Following this, several ¹⁸F-labelled FMZ tracers, including 5-(2′-[18F]fluoroethyl) flumazenil (¹⁸F-FEFMZ), 3-(2′-[¹⁸F]fluoroflumazenil (¹⁸F-FFMZ), 5-(2’-[18F]fluoroethyl)flumazenil (¹⁸F-FEF) and [18F]flumazenil (¹⁸F–FMZ) have been developed.⁵⁵-⁶⁰ Compared to ¹¹C-FMZ, ¹⁸F-FEFMZ has lower receptor affinity, and higher nonspecific binding due to faster metabolism and faster kinetics. ¹⁸F-FFMZ also has faster kinetics than ¹¹C-FMZ. Compared to ¹¹C-FMZ, ¹⁸F-FEF has lower affinity to benzodiazepine receptors, rapid kinetics in the brain and faster metabolism.⁵⁵-⁶⁰¹⁸F-FMZ, with an identical structure to ¹¹C-FMZ, has been shown to have similar pharmacokinetics and peripheral metabolism and PET imaging characteristics as ¹¹C-FMZ.

¹⁸F-FMZ has been established as the tracer of choice for patients with refractory epilepsy in some neurological centres in Europe. PET/CT imaging using flumazenil tracers identify a more restricted region of abnormality in the epileptogenic zone than ¹⁸F-FDG PET/CT.⁶¹ In comparison to ¹⁸F-FDG PET/CT scans benzodiazepine-receptor scans appears “sharper” (Figure 2, 3).

Figure 2

Figure 3

Imaging protocol for PET/CT with ¹⁸F-labelledflumazenil radiotracers is almost similar to protocol for ¹⁸F-FDG PET/CT, except no serum glucose level measurement is required. All flumazenil tracers bind non-selectively to all benzodiazepine receptor subtypes, so pre-treatment with unlabelled flumazenil can result in reduced tracer uptake on benzodiazepine receptors. As a young modality, benzodiazepine-receptor PET imaging is still strengthening its place in neurology.

Functional information delivered by PET and the morphologic information delivered by CT or MR are essential in presurgical evaluation of epilepsy. Nowadays ¹⁸F-FDG PET/CT is a routinely performed imaging modality in localization of the ictal onset zone in patients with refractory epilepsy who are unresponsive to medication therapy. Unfortunately, ¹⁸F-FDG is not an ideal PET tracer regarding the management of patients with epilepsy: areas of glucose hypometabolism do not correlate precisely with the proven degree of change within hippocampal sclerosis, as observed by histopathology or MRI. Benzodiazepine-receptor imaging is a promising alternative in nuclear medicine imaging of epileptogenic focus. The use of ¹¹C-FMZ in clinical practice has been limited by its short half-life and necessitating an on-site cyclotron for production. Therefore, ¹⁸F-FMZ might be established as one of the tracers of choice for patients with refractory epilepsy because of better sensitivity and anatomical resolution.

Multiple new PET tracers for presurgical evaluation of patients with epilepsy are still under preclinical investigations; tracers for neurotransmitter and neuromodulator systems, including the GABA, serotonin, dopamine, glutamate, acetylcholine, adenosine and opioid systems.