In vivo cerebral metabolism and central benzodiazepine-receptor binding in temporal lobe epilepsy

Positron emission tomography measured interictal cerebral glucose metabolism with [18F]fluorodeoxyglucose and central benzodiazepine-receptor binding with [11C]flumazenil in 10 mesial temporal lobe epilepsy (TLE) patients and in normal subjects. Eight TLE patients had mesial temporal, lateral temporal, and thalamic hypometabolism ipsilateral to EEG ictal onsets, with additional extratemporal hypometabolism in four. One had unilateral anterior mesial temporal hypometabolism only, and one had normal metabolism. Each patient had decreased benzodiazepine-receptor binding in the ipsilateral anterior mesial temporal region, without neocortical changes. Thus, interictal metabolic dysfunction is variable and usually extensive in TLE, whereas decreased central benzodiazepine-receptor density is more restricted to mesial temporal areas. Metabolic patterns in TLE may reflect diaschisis, while benzodiazepine-receptor changes may reflect localized neuronal and synaptic loss that is specific to the epileptogenic zone. [11C]Flumazenil imaging may be useful in presurgical evaluation of refractory complex partial seizures.     

Single-chain Fv with manifold N-glycans as bifunctional scaffolds for immunomolecules

PURPOSE: To investigate the significance of cortical pathology of tonic spasms in patients with tuberous sclerosis. METHODS: The subjects were 38 patients with epilepsy associated with tuberous sclerosis. We analyzed ictal EEGs of tonic spasms and partial seizures by means of video-EEG monitoring for a total of 763 tonic spasms in 20 patients and 107 partial seizures in 15 patients. We also investigated the relation between partial seizures and magnetic resonance imaging (MRI) findings of these patients. RESULTS: Ictal EEG patterns of tonic spasms were divided into generalized and focal patterns. Thirteen patients had only generalized patterns, whereas seven had both patterns. In five patients who had focal ictal patterns of tonic spasms and partial seizures, the location of focal patterns corresponded with the location of onset of partial seizures. Focal discharges were seen immediately before, after, and in the middle of tonic spasms in series in 13 patients. The location of focal discharges also corresponded with the location of the onset of partial seizures in 10 of the 13 patients. Regarding partial seizures, four patients had multiple active epileptogenic foci during the same period, and two others had shifting epileptogenic foci with increasing age. CONCLUSIONS: These findings indicate that cortical pathology plays an important role in the occurrence not only of partial seizures but also of tonic spasms in patients with tuberous sclerosis.     

Significance of head turn sequences in temporal lobe onset seizures

We studied head turning in 239 complex partial seizures with or without generalization, in 32 patients with unilateral temporal lobe epilepsy. Head turns occurred in 73% of seizures that did not evolve to focal jerking or secondary generalization, and in all 41 seizures that secondarily generalized. In seizures without focal jerking or secondary generalization the most common pattern was that of single head turns (70%) which were ipsilateral to the focus in 94%. The next most common pattern was that of two or more head turns, with the first two turns in the same direction (19%), always ipsilateral to the focus. In seizures with secondary generalization, the most common sequence was that of two head turns contralateral to each other (59% of seizures). The first was always ipsilateral to the focus, associated with dystonic posturing in 96%, and was not tonic in character. The second was always contralateral, was tonic in character, and was still present within five seconds of secondary generalization or focal jerking. Our results suggest different patterns and sequences of head turning temporal lobe complex partial seizures without, and those with focal jerking or secondary generalization. Some sequences have powerful lateralizing value that can complement other lateralizing features.     

Neuron loss localizes human temporal lobe epilepsy by in vivo proton magnetic resonance spectroscopic imaging

Temporal lobe epileptogenic foci were blindly localized in 8 patients with medically refractory unilateral complex partial seizures using noninvasive in vivo proton magnetic resonance spectroscopic imaging (1H-MRSI) with 4-ml effective voxel size. The brain proton metabolite signals in 8 matched normal controls were bilaterally symmetrical within +/- 10%. The hippocampal seizure foci had 21 +/- 5% less N-acetyl aspartate signal than the contralateral hippocampal formations (p < 0.01). The focal N-acetyl aspartate reductions were consistent with pathology findings of mesial temporal sclerosis with selective neuron loss and gliosis in the surgically resected epileptogenic foci. Proton MRSI correctly localized the seizure focus in all 8 cases. By comparison, MR imaging correctly localized 7 of 8 cases and single photon emission computed tomography correctly localized 2 of 5 cases. No lactate was detected in these interictal studies. No significant changes in choline or creatine were observed. In conclusion, 1H-MRSI is a useful tool for the noninvasive clinical assessment of intractable focal epilepsy. These preliminary results suggest that 1H-MRSI can accurately localize temporal lobe epileptogenic foci.     

Scalp-recorded, ictal focal DC shift in a patient with tonic seizure

PURPOSE: We recorded focal ictal DC shifts from scalp electrodes in a 9-year-old boy with intractable, clinically generalized tonic seizures. The patient had a high intensity signal abnormality of the left temporal cortex with thickening of the gyri on T2-weighted MRI. METHODS: Scalp digital EEGs were recorded using electrodes made of silver/silver chloride. The low frequency filter (LFF) was set at 0.016 Hz. Recorded seizures were subsequently analyzed with LFF settings of 1.0, 0.016 and 0.03 Hz. RESULTS: All recorded seizures initially showed diffuse, low voltage, high frequency activity (electrodecremental pattern) followed 10-20 s later by quasirhythmic activity over the left frontotemporal region. In two seizures, LFF of 0.016-0.03 Hz revealed a slow negative shift over the left frontotemporal area simultaneously with onset of the bilateral electrodecremental pattern. However, in the other seizures, this initial slow negative shift was obscured by artifacts. Subsequent electrocorticography (ECoG) delineated frequent epileptiform discharges in the left temporal as well as frontal cortex. CONCLUSIONS: Scalp-recorded ictal DC shifts may help identify focal epileptogenic brain area in patients with clinically generalized seizures although the technique is vulnerable to artifact.     

Metabolic anatomy of focal motor seizures

Contralateral focal seizures occurred in rats following the intracortical injection of penicillin into the anterior motor cortex. The anatomic dimensions of the metabolic response in the focus as well as the spread of increased activity through the brain were studied by autoradiography following intravenous injection of carbon 14-labeled 2-deoxyglucose. Injections of 25 to 200 units of penicillin resulted in mild to severe contralateral motor jerks coincident with repetitive single spike discharges on the electroencephalogram. Concurrent autoradiography revealed a 1.3- to 2.5-fold increase in metabolic activity in discrete areas in ipsilateral cortex, basal ganglia, thalamus, and contralateral cerebellum. Intracortical injections of over 300 units resulted in the development of recurrent contralateral tonic-clonic seizures, with 20% becoming bilateral. In brains of these animals there was activation of bilateral medial frontal cortex, bilateral extrapyramidal system, thalamus, cerebellum, and limbic structures.     

EEG findings in frontal lobe epilepsies

As a group, epilepsies of frontal lobe origin are thought to be poorly localized using surface EEG recordings. This finding may depend on the specific areas of frontal lobe from which the seizures originate or the pathologic substrate. We reviewed the presurgical surface EEGs of patients with frontal lobe epilepsy who underwent epilepsy surgery. The specific area of the frontal lobe where seizures originated was determined by 1) intracranial ictal EEG recordings, or 2) the presence of a structural lesion, identified by imaging studies in patients who achieved complete seizure control following surgery. We differentiated patients whose seizures began in the dorsolateral frontal convexity from those whose seizures began in the medial frontal region, and we correlated EEG findings in the interictal, postictal, and ictal states with seizure semiology, pathologic substrate, and surgical outcome. Four of nine patients had seizures originating in the dorsolateral frontal convexity and five had medial frontal onset seizures. Patients whose seizures originated from the dorsolateral convexity had focal interictal epileptiform abnormalities that localized to the region of seizure onset. Patients whose seizures began in the medial frontal region had either no interictal epileptiform abnormality or had multifocal epileptiform discharges. Patients whose seizures began in the dorsolateral convexity showed focal electrographic seizure activity that was localizing. This rhythmic fast activity did not appear to be substrate-specific. Patients whose seizure onset localized to the medial frontal region did not show focal electrographic seizure at clinical onset. We conclude that the scalp EEG recordings of frontal lobe epilepsies contain features that enable differentiation of seizures originating from two different regions of the frontal lobe.     

A role for the bilateral involvement of perirhinal cortex in generalized kindled seizure expression

The perirhinal cortex (PRh) has been suggested as a substrate for the expression of generalized clonic seizures in the late stages of kindling development (stages 4-5). Using the induction of Fos as a marker of neuronal activation, the PRh region was investigated after kindling or nonkindling electrical stimulation. Nonkindling electrical stimulation of the PRh elicited stimulus-locked behaviors, without afterdischarge. These behaviors were characterized by rearing and bilateral forelimb clonus which were terminated upon electrical stimulus offset in half of the rats displaying this behavior (with the other half expressing self-sustained seizures). In these animals, Fos immunoreactivity was found throughout neocortical and subcortical structures in the hemisphere ipsilateral to the stimulating electrode. By contrast, Fos-immunoreactivity in the contralateral hemisphere was localized primarily in the PRh and frontal motor cortex. Likewise, similar patterns of Fos immunoreactivity were observed in both hemispheres of rats following kindling to one generalized clonic seizure from several limbic and paleocortical structures. These results suggest that the bilateral involvement of the PRh is critical in producing the bilateral behaviors associated with generalized clonic seizure expression. In support of this interpretation, infusion of 3 M KCl directly into the contralateral PRh of rats kindled to a single stage 4-5 (generalized clonic) seizure from the ipsilateral amygdala reduced seizure manifestations from a generalized clonic seizure (stage 4-5) to a unilateral clonic seizure (stage 3) without affecting measures of focal excitability. Taken together, these data indicate a role for the bilateral involvement of the PRh in generalized clonic seizure expression whether evoked from the naive or kindled state. These results further indicate that bilateral behaviors require the bilateral involvement of the structures necessary for the expression of these behaviors.     

Normal and pathological aging--findings of positron-emission-tomography

Normal aging of the brain is predominantly characterized by metabolic changes in the prefrontal cortex. While in middle age there is a trend to hyperfrontality, PET demonstrates in old age a decline of regional cerebral glucose metabolism in frontal areas. In progeric diseases, clinically apparent as premature aging, the metabolic pattern is similar like in normal aging but qualitatively more severe. In patients with the diagnosis of probable Alzheimer's disease (AD) hypometabolism in early dementia is typically present in heteromodal association areas. Hypometabolism then spreads to other cortical and subcortical regions suggesting a characteristic pattern of degeneration that reflects selective vulnerability within limbic-cortical networks. Synaptic plasticity, clinically apparent as cognitive reserve capacity, can be assessed by PET under specific cognitive activation. In AD it is reduced in comparison to age-matched normals and may be influenced by drugs giving trophic support to neurochemical systems.     

Rolandic type cerebral palsy in children as a pattern of hypoxic-ischemic injury in the full-term neonate

Magnetic resonance images (MRIs) of the brains of 11 patients aged from 1 week to 12 years with a distinctive type of cerebral palsy were selected based on distribution of cerebral lesions, which were restricted to bilateral perirolandic cortical and subcortical regions, including frequent symmetric involvement of basal ganglia and ventrolateral nucleus of thalami. Retrospectively, the perinatal history and clinical features were reviewed to correlate clinical data with this distinctive pattern of brain injury. Clinically affected neonates had an encephalopathy associated with a severe perinatal asphyxial event. Older children with cerebral palsy survived a similar perinatal course and demonstrated spastic quadriparesis with bulbar or pseudobulbar involvement, lack of verbal speech and variable delays in cognitive development. The distribution of hypoxic-ischemic lesions involving bilateral perirolandic regions, basal ganglia, and thalami, appears to correlate with increased metabolic areas of primary myelination in full-term neonates, but not with arterial border zones nor a single cerebral artery distribution. Myelination is a critical process in maturing brain associated with marked increase in tissue respiration and thus greater susceptibility to oxygen deprivation. It is believed that the extent of hypoxic-ischemic brain injury is determined principally by brain maturity and regional metabolic rates at time of insult and this correlates with active myelination in full-term neonates. This study confirms previous data from neuropathologic literature and recent reports of neuroimaging studies of asphyxiated neonates. In addition, retrospective analysis of the clinical data enables recognition of a type of cerebral palsy that might be the hallmark of hypoxic-ischemic injury in term neonates.     

18F-labeled 2-deoxy-2-fluoro-D-glucose positron-emission tomography scans for the localization of the epileptogenic foci

The localization of epileptogenic foci that are amenable to curative epilepsy surgery may be accomplished by noninvasive surface electroencephalogram (EEG) recordings, clinical observations, computed tomography (CT), magnetic resonance imaging (MRI), and neuropsychologic tests. Other tests, such as invasive EEG, 18F-fluoro-deoxyglucose-positron-emission tomography (FDG-PET or PET) scans, and single-photon-emission computed tomography (SPECT) scans, have also been used at various epilepsy centers to help identify candidates who might benefit from such surgery. Interictal PET scans have demonstrated hypometabolism in areas concordant with the epileptogenic foci indicated by other diagnostic tests such as EEG and MRI. However, PET scans have also shown no abnormality in many patients with EEG-indicated epileptogenic foci; in others, the scans have shown abnormal metabolism in areas that were discordant with the epileptogenic foci. Although substitution of the noninvasive PET scan for the invasive EEG recordings would be desirable, the available data were insufficient to determine whether PET scans might serve as a reliable substitute for EEG. A positive PET scan might contribute independent information for identifying the epileptogenic site but could be noncontributory or confusing when hypometabolism is not seen or is seen in presumably normal brain areas. It is not evident from the data in the literature to what extent confirmatory PET scan findings might contribute to the management of patients with complex partial seizures.     

An anatomo-clinical case of dementia in endovascular large-cell lymphoma

Cerebral angiotropic large cell lymphoma is a rare fatal neurologic disorder characterized by multifocal intravascular proliferation of large pleomorphic cells within vessels of all caliber, predominantly skin and nervous system. Clinical manifestations in previously reported cases were dominated by focal neurologic signs, epilepsia and progressive dementia. We report a case of a 70 year-old man with subacute dementia, epileptic seizures and cerebrovascular events. There was no evidence of a systemic disease outside the nervous system. Cerebrospinal fluid contained 13 leukocytes/mm3 (49% of lymphocytic cells) and more than 100 mg/dl of protein. Cytology was negative. Cranial MRI demonstrated cerebral atrophy and an increased paraventricular signal in T 2 weighted images. A frontal brain biopsy revealed only neuronal dystrophy and astrocytic gliosis. Despite treatment with corticosteroids the patient died 18 months after the onset of the first symptoms. Autopsy was performed and revealed B cell lymphoma.     

Sex differences in patients with mesial temporal lobe epilepsy

Possible sex differences in the pattern of interictal hypometabolism were investigated, and also seizure spread in patients with mesial temporal lobe epilepsy (n=48) and hippocampal sclerosis (MTLE). Male patients (n=21) more often had a frontal lobe hypometabolism ipsilateral to the seizure onset (p<0.0001) and a spread of epileptiform activity to this region (p=0.001). By contrast, female patients more often exhibited hypometabolism (p=0.0052) and an ictal spread to the contralateral temporal lobe (p=0.0097). These findings suggest sex differences in spatial distribution of brain dysfunction in MTLE, perhaps reflecting sexual dimorphism in regional cerebral connectivity.     

A crucial role of the alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid subtype of glutamate receptors in piriform and perirhinal cortex for the initiation and propagation of limbic motor seizures

The role of alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptors in the initiation and propagation of limbic motor seizures in rats was examined by the intracerebral and systemic administration of 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo (f) quinoxaline (NBQX), a selective antagonist of the AMPA subtype of glutamate receptor. Limbic motor seizures were evoked focally by the application of the gamma-aminobutyric acid receptor antagonist, bicuculline, into area tempestas, an epileptogenic site in the deep anterior piriform cortex. Before eliciting seizures, NBQX was applied focally into either 1) area tempestas or 2) perirhinal or posterior piriform cortex ipsilateral to the area tempestas from which seizures were evoked. In addition, pretreatment with i.p. NBQX was evaluated for anticonvulsant actions against area tempestas-evoked clonic or systemically evoked tonic seizures. In all conditions, a dose-dependent decrease in the severity of seizures was obtained with NBQX. With focal intracerebral administration, a dose of 500 pmol of NBQX consistently protected against limbic motor seizures, with partial protection achieved with 100 pmol. After i.p. administration, 2.5 and 5.0 mg/kg significantly protected the rats from both limbic motor seizures and tonic extensor seizures. No overt disturbance of spontaneous behavior was associated with the anticonvulsant doses of NBQX. Moreover, both forebrain substrates of limbic motor seizures and hindbrain substrates of tonic extensor seizures were highly susceptible to disruption by NBQX. The results indicate that AMPA subtype of glutamate receptors are crucial mediators of seizure propagation via perirhinal and piriform cortics.     

Nucleus reticularis thalami and neocortical paroxysms in the rat

The role of the nucleus reticularis thalami in spike-wave discharges in rats with genetic absence epilepsy has already been demonstrated. This study further investigated the role of the nucleus reticularis thalami in paroxysmal synchronizations in Sprague-Dawley rats; this strain shows no propensity to epileptic activity. Electroencephalographic patterns were followed in chronically implanted, unrestrained rats. After both electrolytic and chemical unilateral lesions, stereotaxically placed in the anterolateral sectors of this nucleus (verified post mortem), abnormal electroencephalographic rhythms (high-voltage polyspikes and spike-wave complexes) were recorded from the frontoparietal cortex, primarily in the contralateral hemisphere. Stereotyped discharges at 3 Hz developed progressively from multiple spikes within the alpha frequency range through the lengthening of the wave component. The excessive synchronized activity recorded from the intact hemisphere was of greater amplitude and occurred slightly earlier than from the lesioned hemisphere. These EEG patterns were associated with behavioural manifestations closely resembling those seen during absence seizures in humans. Bilateral lesions did not induce paroxysmal activity, both hemispheres being characterized by dominant delta/theta activity without signs of EEG-synchronized sleep. The seizures may thus have been due to disinhibition of the contralateral reticularis nucleus, recently shown to project to the reticularis nucleus of the other side in rats. This working hypothesis is supported by callosal cuts. The results indicate that the reticular neurons exert a control over neocortical paroxysmal activity even in animals which do not present genetic absence epilepsy.     

Adaptive and maladaptive behaviour in children with epileptic encephalopathies: correlation with cerebral glucose metabolism

In the childhood epileptic encephalopathies mental impairment is common and severe. Traditional cognitive assessment is difficult because of the low level of performance, autistic features, and the unpredictable effect of seizures. An alternative is to measure adaptive and maladaptive behaviour using instruments administered to the caregivers. Adults with different types of dementia have characteristic patterns of cortical glucose hypometabolism. Thirty-two children were studied using visual and semiquantitative analysis of 18fluorodeoxyglucose positron emission tomographic (PET) scans. The Vineland Scales and the Conners' Questionnaires were used to assess adaptive and maladaptive behaviour. The mean adaptive behaviour composite score was 37.3+/-15.6; all but one subject had a low adaptive level. A profile of relative strength in socialisation and weakness in daily living skills emerged. Up to two-thirds of children had abnormal behaviour patterns, particularly attention-deficit disorders and hyperactivity. Adaptive and maladaptive behaviour was not related to the presence or absence of focal cortical PET abnormalities. However, adaptive behaviour scores showed an inverse correlation with the degree of metabolic abnormality in the frontal lobes.     

Electroencephalographic findings and occurence of seizures after surgery of the Gasserian ganglion

The results of EEG investigations after Spiller-Frazier's operation for trigeminal neuralgia in 112 patients are reported. Follow-up EEGs were recorded within 1-8 years after surgery; two to three follow-up tracings were available in 53 patients. Two distinct phases of EEG alterations were noted: 1) The immediate postoperative phase characterized by bilateral delta waves of maximal distribution in the frontal-precentral area and in the temporal area on the side of surgery. Such alterations are supposedly due to postoperative edema or associated metabolic disturbances. 2) Several months after surgery focal abnormalities of the temporal lobe develop, which consist of high amplitude alpha-, beta- or theta-waves, sharp waves, spikes and occasional stypical spike-and-wave complexes. These abnormalities are reflected on the contralateral side in approximately one third of the case. Repeated EEGs confirmed the consistency of degree and location of these findings with the exception of a less constant incidence of spikes and sharp waves. Severity of EEG abnormalities and incidence of potentially epileptogenic discharges increases with age. In spite of the precarious location of such focal abnormalities in the temporal lobe only 3 of 112 patients (2.7%) reported seizures with temporal lobe features. The age of the three patients was below the average age of 59.1 years. Seizures occurred sporadically beginning approximately 2 years after surgery. The low incidence of seizures may in our opinion be due to the advanced age of most patients.     

Widespread functional deficits in perception-related networks demonstrated by PET in a case with simple visual seizures

PURPOSE: To study benzodiazepine receptor (BZR) density and functional deficits in occipital lobe epilepsy. METHODS: A 39-year-old man who had simple partial visual seizures after neurosurgical transtentorial extirpation of a pinealoma was studied by EEG, magnetic resonance imaging (MRI), and positron emission tomography (PET) of [18F]2-fluoro-2-deoxy-D-glucose (FDG) at rest and during visual activation task and[11C]flumazenil (FMZ). RESULTS: Electroencephalographic recordings were nonspecific, and MRI did not reveal any morphologic anomaly in the occipital lobe. Flumazenil-PET demonstrated a small epileptogenic region in the right visual association cortex and FDG-PET showed hypometabolism in a corresponding location and thalamic diaschisis. Stimulation of occipital metabolism by a continuous visual recognition task improved significantly the contrast between the dysfunctional zone and its surround. CONCLUSIONS: As BZR deficits are restricted to a small region, widespread hypometabolism in networks involved in visual information processing indicates an extensive functional deactivation by the epileptogenic focus.     

Semiological seizure classification

We propose an epileptic seizure classification based exclusively on ictal semiology. In this semiological seizure classification (SSC), seizures are classified as follows: a. Auras are ictal manifestations having sensory, psychosensory, and experiential symptoms. b. Autonomic seizures are seizures in which the main ictal manifestations are objectively documented autonomic alterations. c. "Dialeptic" seizures have as their main ictal manifestations an alteration of consciousness that is independent of ictal EEG manifestations. The new term "dialeptic" seizure has been coined to differentiate this concept from absence seizures (dialeptic seizures with a generalized ictal EEG) and complex partial seizures (dialeptic seizures with a focal ictal EEG). d. Motor seizures are characterized mainly by motor symptoms and are subclassified as simple or complex. Simple motor seizures are characterized by simple, unnatural movements that can be elicited by electrical stimulation of the primary and supplementary motor area (myoclonic, tonic, clonic and tonic-clonic, versive). Complex motor seizures are characterized by complex motor movements that resemble natural movements but that occur in an inappropriate setting ("automatisms"). e. Special seizures include seizures characterized by "negative" features (atonic, astatic, hypomotor, akinetic, and aphasic seizures). The SSC identifies in detail the somatotopic distribution of the ictal semiology as well as the seizure evolution. The advantages of a pure SSC, as opposed to the current classification of the International League Against Epilepsy (ILAE), which is actually a classification of electroclinical syndromes, are discussed.     

Direct isolation, phenotyping and cloning of low-frequency antigen-specific cytotoxic T lymphocytes from peripheral blood

A 21-year-old male presented with temporal lobe epilepsy associated with a venous angioma in the ipsilateral frontal lobe, presenting as intractable complex partial seizures. Neuroimaging showed a cerebral venous angioma in the right dorsolateral and opercular frontal lobe, and atrophy of the right hippocampus. As the ictal electroencephalogram (EEG) obtained with subdural electrodes indicated spike discharges initiating from the right mesial temporal lobe, temporal lobectomy was performed. The patient was seizure-free after the operation. Patients with epilepsy who have a cerebral venous angioma require precise analysis of the seizure pattern and an ictal EEG because of cerebral venous angioma may be associated with an another epileptogenic lesion which is surgically treatable.