Karolien Goffin

Paroxysmal exercise-induced dyskinesia and epilepsy is due to mutations in SLC2A1, encoding the glucose transporter GLUT1

Paroxysmal exercise-induced dyskinesia (PED) can occur in isolation or in association with epilepsy, but the genetic causes and pathophysiological mechanisms are still poorly understood. We performed a clinical evaluation and genetic analysis in a five-generation family with co-occurrence of PED and epilepsy (n = 39), suggesting that this combination represents a clinical entity. Based on a whole genome linkage analysis we screened SLC2A1, encoding the glucose transporter of the blood-brain-barrier, GLUT1 and identified heterozygous missense and frameshift mutations segregating in this and three other nuclear families with a similar phenotype. PED was characterized by choreoathetosis, dystonia or both, affecting mainly the legs. Predominant epileptic seizure types were primary generalized. A median CSF/blood glucose ratio of 0.52 (normal >0.60) in the patients and a reduced glucose uptake by mutated transporters compared with the wild-type as determined in Xenopus oocytes confirmed a pathogenic role of these mutations. Functional imaging studies implicated alterations in glucose metabolism in the corticostriate pathways in the pathophysiology of PED and in the frontal lobe cortex in the pathophysiology of epileptic seizures. Three patients were successfully treated with a ketogenic diet. In conclusion, co-occurring PED and epilepsy can be due to autosomal dominant heterozygous SLC2A1 mutations, expanding the phenotypic spectrum associated with GLUT1 deficiency and providing a potential new treatment option for this clinical syndrome.

Cyclicity of spontaneous recurrent seizures in pilocarpine model of temporal lobe epilepsy in rat

Pilocarpine administration to rats results in status epilepticus (SE) and after a latency period to the occurrence of spontaneous seizures. The model is commonly used to investigate mechanisms of epileptogenesis as well as the antiepileptic effects of novel compounds. Surprisingly, there have been no video-EEG studies determining the duration of latency period from SE to the appearance of the first spontaneous seizures or the type and frequency of spontaneous seizures at early phase of pilocarpine-induced epilepsy even though such information is critical for design of such studies. To address these questions, we induced SE with pilocarpine in 29 adult male Wistar rats with cortical electrodes. Rats were continuously video-EEG monitored during SE and up to 23 days thereafter. The first spontaneous seizures occurred 7.2+/-3.6 days after SE. During the follow-up, the mean daily seizure frequency was 2.6+/-1.9, the mean seizure duration 47+/-7 s, and the mean behavioral seizure score 3.2+/-0.9. Typically first seizures were partial (score 1-2). Interestingly, spontaneous seizures occurred in clusters with cyclicity, peaking every 5 to 8 days. These data show that in the pilocarpine model of temporal lobe epilepsy the latency period is short. Because many of the early seizures are partial and the seizures occur in clusters, the true phenotype of epilepsy triggered by pilocarpine-induced SE may be difficult to characterize without continuous long-term video-EEG monitoring. Finally, our data suggest that the model can be used for studies aiming at identifying the mechanisms of seizure clustering.

The use of SPECT and PET in routine clinical practice in epilepsy.

Purpose of reviewThe aim of this article is to give a subjective review of the usefulness of single photon emission computed tomography (SPECT) and positron emission tomography (PET) imaging in clinical practice in epilepsy for 2007. Recent findingsBoth ictal perfusion SPECT and interictal fluorodeoxyglucose PET can provide new information in the presurgical evaluation of intractable partial epilepsy. These functional imaging modalities reflect dynamic seizure-related changes in cerebral cellular functions. Although asymmetry of fluorodeoxyglucose PET metabolism has been useful to localize the epileptic temporal lobe, which tends to be more hypometabolic than the contralateral one, both frontal lobes are more hypometabolic than the epileptic temporal lobe, and may represent a region of ‘surround inhibition’. Due to its low temporal resolution, ictal perfusion SPECT hyperperfusion patterns often contain both the ictal onset zone and propagation pathways. These patterns often have a multilobulated ‘hourglass’ appearance. The largest and most intense hyperperfusion cluster often represents ictal propagation, and does not always need to be resected in order to render a patient seizure free. SummaryOptimized interictal FDG-PET and ictal perfusion SPECT as part of a multimodality imaging platform will be important tools to better understand the neurobiology of epilepsy and to better define the epileptogenic, ictal onset, functional deficit and surround inhibition zones in refractory partial epilepsy.

Neuronuclear Assessment of Patients With Epilepsy

Epilepsy is a common chronic neurological disorder that is controlled with medication in approximately 70% of cases. When partial seizures are recurrent despite the use of antiepileptic drugs, resection of the epileptogenic cortex may be considered. Nuclear medicine plays an important role in the presurgical assessment of patients with refractory epilepsy. Single-photon emission computed tomography (SPECT) and positron emission tomography (PET) techniques are used to determine the seizure onset zone, which needs to be resected to render a patient seizure free. Correct localization of the ictal onset zone with the use of SPECT or PET is associated with a better surgical outcome. Ictal perfusion SPECT imaging with (99m)Tc-ethyl cysteinate dimer (ECD) or (99m)Tc-hexamethylpropyleneamine oxime (HMPAO) enables one to detect the seizure onset zone in a majority of cases, especially in patients with temporal lobe epilepsy. Interictal SPECT imaging, which is more widely available, is unreliable to determine the ictal onset zone and is usually only used for comparison with ictal SPECT images. Assessment of the ictal onset zone using subtracted ictal and interictal studies, overlayed on structural imaging has proven to be more sensitive and more specific compared with visual assessment. Video-electroencephalography monitoring in combination with ictal SPECT imaging, however, is only available in specialized centers. It is important to inject the perfusion tracer as early as possible after the beginning of a seizure and to be aware of patterns of seizure propagation. Interictal (18)F-fluorodeoxyglucose (FDG)-PET is routinely used to detect brain areas of hypometabolism, which usually encompass, but tend to be larger than, the seizure onset zone. Also, for assessment of FDG-PET, it is advisable to use an automated technique comparing the patients images to a normal database in addition to visual interpretation of the images, since automated techniques have proven to be more accurate. In view of the thickness of the cortical ribbon, which may be below the resolution of the PET camera, posthoc partial volume correction or PET reconstruction incorporating the anatomical information of magnetic resonance imaging (MRI), may be useful for optimal assessment of glucose metabolism. Perfusion SPECT and interictal FDG-PET are able to demonstrate areas of abnormal perfusion and metabolism at a distance from the ictal onset zone, which may be associated with cognitive and psychiatric comorbidities, and may represent the functional deficit zone in epilepsy. Part of the functional deficit zone is a dynamic seizure-related process, which may resolve with cessation of seizures. In recent years, novel PET tracers have been developed to visualize not only glucose metabolism but also a wide variety of specific receptor systems. In patients with epilepsy, changes in the gamma-amino-butyric acid(A) receptor, opioid receptor, 5-HT(1A) serotonin receptor, nicotinic acetylcholine receptor systems, and others have been described. Because these tracers are not widely available and the superiority of studying these receptor systems over glucose metabolism in the presurgical evaluation of patients with refractory epilepsy remains to be proven, their use in clinical practice is limited at the moment. Finally, advances in small animal PET scanning allow the in vivo study of the process of epileptogenesis, starting from an initial brain insult to the development of seizures, in animal models of epilepsy. Potential new therapeutic targets may be discovered using this translational approach.

Single-photon emission tomography

Single-photon emission computed tomography (SPECT) is a functional nuclear imaging technique that allows visualization and quantification of different in vivo physiologic and pathologic features of brain neurobiology. It has been used for many years in diagnosis of several neurologic and psychiatric disorders. In this chapter, we discuss the current state-of-the-art of SPECT imaging of brain perfusion and dopamine transporter (DAT) imaging. Brain perfusion SPECT imaging plays an important role in the localization of the seizure onset zone in patients with refractory epilepsy. In cerebrovascular disease, it can be useful in determining the cerebrovascular reserve. After traumatic brain injury, SPECT has shown perfusion abnormalities despite normal morphology. In the context of organ donation, the diagnosis of brain death can be made with high accuracy. In neurodegeneration, while amyloid or (18)F-fluorodeoxyglucose positron emission tomography (FDG-PET) are the nuclear diagnostic tools of preference for early and differential diagnosis of dementia, perfusion SPECT imaging can be useful, albeit with slightly lower accuracy. SPECT imaging of the dopamine transporter system is widely available in Europe and Asia, but since recently also in the USA, and has been accepted as an important diagnostic tool in the early and differential diagnosis of parkinsonism in patients with unclear clinical features. The combination of perfusion SPECT (or FDG-PET) and DAT imaging provides differential diagnosis between idiopathic Parkinsons disease, Parkinson-plus syndromes, dementia with Lewy bodies, and essential tremor.

Gender-dependent increases with healthy aging of the human cerebral cannabinoid-type 1 receptor binding using [(18)F]MK-9470 PET.

The endocannabinoid system (ECS) is implicated as a regulator of homeostasis of several cerebral functions and is a novel target for drug treatment of neuropyschiatric disorders. So far, the cerebral cannabinoid-type 1 receptor (CB1R) has only been studied using in vitro, animal model, electrophysiological and post-mortem data. We have used positron emission tomography (PET) using a high-affinity, subtype-selective radioligand, [(18)F]MK-9470, to assess the in vivo cerebral CB1R distribution and its variation with healthy aging and gender. Fifty healthy volunteers (25 M/25 F, 18-69 years) underwent [(18)F]MK-9470 PET. Parametric [(18)F]MK-9470 binding maps were constructed, corrected for partial volume effects and analyzed using statistical parametric mapping in a combined categorical (gender) and covariate (age) design. We found that [(18)F]MK-9470 binding to CB1R increased with aging but only in women (p(FWE)<0.05, corrected for multiple comparisons); this was most pronounced in the basal ganglia, lateral temporal cortex and limbic system, especially in the hippocampus. Men showed higher [(18)F]MK-9470 binding then women (p<0.001, uncorrected), in clusters of the limbic system and cortico-striato-thalamic-cortical circuit. Region-dependent and gender-related upregulation of [(18)F]MK-9470 binding with aging is in line with ex vivo findings in rodent studies and may be associated with a changing homeostatic capacity or compensation mechanisms in the ECS that is modulated by sex hormones. In vivo PET of the CB1R will likely improve our understanding of the ECS in several neurological and psychiatric disorders.

Regional changes in type 1 cannabinoid receptor availability in Parkinson's disease in vivo

The type 1 cannabinoid receptor (CB1) is a crucial modulator of synaptic transmission in brain and has been proposed as a potential therapeutic target in Parkinsons disease (PD), especially for treatment of levodopa-induced dyskinesias (LID). Our aim was to measure CB1 levels in brains of PD patients in vivo and to investigate the relation between CB1 availability and LID. We studied 12 healthy controls and 29 PD patients (9 drug-naïve patients with early PD, 10 patients with advanced PD and LID, and 10 patients with advanced PD without LID). PD patients were examined using the Unified Parkinsons Disease Rating Scale (UPDRS) and the modified Abnormal Involuntary Movement Scale (mAIMS). All subjects underwent positron emission tomography (PET) with the CB1-selective radioligand [(18)F] MK-9470 and magnetic resonance imaging (MRI). PD patients showed an absolute decrease in CB1 availability in the substantia nigra. By contrast, CB1 availability was relatively increased in nigrostriatal, mesolimbic, and mesocortical dopaminergic projection areas. CB1 availability did not differ significantly between advanced PD patients with and without LID. Within the group of PD patients with LID, there was no significant correlation between CB1 availability and LID severity. These data demonstrate regional changes in CB1 availability in PD in vivo, but do not support a role for dysregulation of CB1 levels in the pathogenesis of LID.

Relationship of Type 1 Cannabinoid Receptor Availability in the Human Brain to Novelty-Seeking Temperament

CONTEXT Brain neurochemistry can partially account for personality traits as a variance of normal human behavior, as has been demonstrated for monoamine neurotransmission. Positron emission tomography using fluorine 18-labeled MK-9470 now enables quantification of type 1 cannabinoid receptors (CB1R) in the brain. OBJECTIVE To investigate whether there is a relationship between human temperament traits and regional cerebral CB1R availability. DESIGN Forty-seven [(18)F]MK-9470 baseline scanning sessions were performed and correlated with the temperament dimensions and subdimensions of the 240-item Cloninger Temperament and Character Inventory. SETTING Academic brain imaging center. PARTICIPANTS Forty-seven nonsmoking, healthy volunteers (paid). Main Outcome Measure Voxel-based correlation of temperament variables of the inventory with regional CB1R availability. RESULTS Novelty seeking was inversely correlated with global CB1R availability (r = -0.33, P = .02), with the most significant correlation in the left amygdala (r = -0.41, P = .005). In particular, the subdimension extravagance showed a highly significant inverse correlation to global CB1R availability (r = -0.53, P <.001), most pronounced in the amygdala, anterior cingulate, parietal cortex, and precuneus. Also, disorderliness was inversely correlated with global CB1R availability (r = -0.31, P = .04). CONCLUSIONS Low baseline cerebral CB1R availability is related to a high novelty-seeking personality, in particular to extravagance, most pronounced in the amygdala. Further investigation of the functional role of the CB1R is warranted in pathological behavior known to be strongly related to novelty seeking, such as addiction and eating disorders.

In vivo activation of endocannabinoid system in temporal lobe epilepsy with hippocampal sclerosis

The endocannabinoid system modulates neuronal excitability, protects neurons against hyperexcitability and is involved in epileptogenesis in animal models of mesial temporal lobe epilepsy with hippocampal sclerosis. We performed in vivo positron emission tomography imaging of the type 1 cannabinoid receptor in patients with mesial temporal lobe epilepsy with hippocampal sclerosis. Twelve patients with refractory mesial temporal lobe epilepsy due to hippocampal sclerosis received a [(18)F]MK-9470 scan to assess type 1 cannabinoid receptor availability in vivo. Parametric modified standard uptake values were used as quantitative measure of type 1 cannabinoid receptor availability and images were spatially normalized to standard space. Voxel-based analysis was performed comparing patients with hippocampal sclerosis to controls and correlations between type 1 cannabinoid receptor status and seizure characteristics were done using volumes of interest. Type 1 cannabinoid receptor positron emission tomography was co-registered with subtraction ictal single photon emission computed tomography co-registered to magnetic resonance imaging of a complex partial seizure (n = 9). An increased type 1 cannabinoid receptor availability in the ipsilateral temporal lobe was observed, which correlated negatively with the latency since last seizure before scanning and positively to the number of seizures in the month before scanning. A decreased type 1 cannabinoid receptor availability was present in the superior insular cortex, ipsilateral more than contralateral. The ipsilateral insular region displayed a mild ictal hyperperfusion in the transition zone of subtraction ictal single photon emission computed tomography co-registered to magnetic resonance imaging temporal lobe hyperperfusion-frontal lobe hypoperfusion during complex partial seizures. Type 1 cannabinoid receptor availability showed opposite changes in different brain regions that are involved during complex partial seizures in refractory mesial temporal lobe epilepsy with hippocampal sclerosis. The increase in type 1 cannabinoid receptor availability at the seizure onset zone might be a protective mechanism of neurons against hyperexcitability and seizure activity, or contribute to the process of epileptogenesis, or both. The decreased type 1 cannabinoid receptor availability in the insula may play a role in surround inhibition and prevention of seizure propagation.

Longitudinal microPET imaging of brain glucose metabolism in rat lithium-pilocarpine model of epilepsy.

The lithium-pilocarpine model of epilepsy in rat has been used extensively to investigate basic mechanisms of epilepsy and mimics human temporal lobe epilepsy. Our aim was to investigate longitudinal alterations in metabolism after lithium-pilocarpine induced status epilepticus (SE) using [(18)F]FDG microPET. Twenty-eight Wistar rats received lithium chloride followed by pilocarpine (n=19) or saline (n=9) IP. Continuous video-EEG was used to monitor SE and occurrence of spontaneous seizures (SS). FDG microPET imaging was performed at baseline, on day 3 after drug administration (D3), and at the end of the monitoring period (CR). MicroPET images were spatially normalized to Paxinos space and parametric standardized uptake value (SUV)-images were generated. Metabolism was compared between groups of animals and between different time points. Eighteen animals developed SE, 11 had died by D3. SS were recorded in 3 of 7 surviving SE animals. On D3, metabolism was reduced in SE group compared to controls throughout the brain (-49+/-27%), except for the cerebellum: mostly in hippocampus, entorhinal cortex and thalamus bilaterally. Metabolism tended to be different between SS and no SS animals on D3 in striatum and hippocampus. In CR condition, relative metabolism was significantly different in SE group compared to controls in cerebellum and brainstem bilaterally and left striatum and entorhinal cortex. There were no significant differences between SS and no SS animals in CR condition. Pilocarpine-induced SE causes a severe, but transient reduction in overall metabolism on D3 in rat brain. Metabolic differences on D3 between SS and no SS animals need further study to investigate potential use as an early marker of epileptogenesis.