Seizures, CSF neurofilament light and tau in patients with subarachnoid haemorrhage.

OBJECTIVES: Patients with severe subarachnoid haemorrhage (SAH) often suffer from complications with delayed cerebral ischaemia (DCI) due to vasospasm that is difficult to identify by clinical examination. The purpose of this study was to monitor seizures and to measure cerebrospinal fluid (CSF) concentrations of neurofilament light (NFL) and tau, and to see whether they could be used for predicting preclinical DCI. METHODS: We prospectively studied 19 patients with aneurysmal SAH who underwent treatment with endovascular coiling. The patients were monitored with continuous EEG (cEEG) and received external ventricular drainage (EVD). CSF samples of neurofilament light (NLF) and total tau (T-tau) protein were collected at day 4 and day 10. Cox regression analysis was applied to evaluate whether seizures and protein biomarkers were associated with DCI and poor outcome. RESULTS: Seven patients developed DCI (37%), and 4 patients (21%) died within the first 2 months. Six patients (32%) had clinical seizures, and electrographic seizures were noted in one additional patient (4.5%). Increased tau ratio (proportion tau10/tau4) was significantly associated with DCI and hazard ratio [HR=1.33, 95% confidence interval (CI) 1.055-1.680. P = .016]. CONCLUSION: Acute symptomatic seizures are common in SAH, but their presence is not predictive of DCI. High values of the tau ratio in the CSF may be associated with development of DCI.

The diagnosis and treatment of limbic encephalitis.

The term limbic encephalitis (LE) was first introduced in 1968. While this disease was initially considered rare and is often fatal with very few treatment options, several reports published in the last decade provide a better description of this condition as well as possible causes and some cases of successful treatment. The clinical manifestation of LE is primarily defined by the subacute onset of short-term memory loss, seizures, confusion and psychiatric symptoms suggesting the involvement of the limbic system. In addition, EEG often shows focal or generalized slow wave or epileptiform activity, and MRI findings reveal hyperintense signals of the medial temporal lobes in T2-weighted or FLAIR images. The current literature suggests that LE is not a single disorder but is comprised of a group of autoimmune disorders predominantly affecting the limbic system. Before the diagnosis of LE can be determined, other causes of subacute encephalopathy must be excluded, especially those resulting from infectious aetiologies. LE has previously been regarded as a paraneoplastic phenomenon associated with the classical onconeuronal antibodies that are primarily directed against intracellular antigens. However, recent literature suggests that LE is also associated with antibodies that are directed against cell surface antigens, and these cases of LE display a much weaker association to the neoplasm. The treatment options for LE largely depend on the aetiology of the disease and involve the removal of the primary neoplasm. Therefore, a search for the underlying tumour is mandatory. In addition, immunotherapy has been successful in a significant number of patients where LE is not associated with cancer.

Empirical evidence of underutilization of referrals for epilepsy surgery evaluation.

BACKGROUND: Epilepsy surgery is a treatment that can cure patients with intractable epilepsy. This study investigates whether referrals for epilepsy surgery evaluation are underutilized. METHODS: Patients with epilepsy aged 18-60 years were identified in a computerized registry held by public health care providers in a Swedish county using ICD codes. Clinical data and data on referral status for epilepsy surgery were obtained from the patients' medical records. Potential candidates for epilepsy surgery evaluation were identified using pre-specified criteria. Obstacles for referral were analysed by comparing clinical data in patients who were considered for referral and those who were not. Appropriateness of non-referral was evaluated against recommendations from the Swedish Council on Technology in Health Care (SBU). RESULTS: Of 378 patients with epilepsy in the registry, 251 agreed to participate. Of 251, 40 were already referred patients and 48 patients were identified as potential candidates for epilepsy surgery evaluation by study criteria. Referral had been considered but not performed in 15 of the potential candidates. Potential candidates not considered for referral were less likely to have seen a neurologist, to have had an EEG, CT and MRI, and more likely to have cognitive disturbances. Following the recommendations by the SBU, 28 of 48 potential candidates were identified as inappropriately not referred patients. CONCLUSION: The number of missed referrals for epilepsy surgery evaluation was estimated to be 60 per 100,000 inhabitants. Several important obstacles were found for not referring patients for epilepsy surgery evaluation.

No apparent effect of surgery for temporal lobe epilepsy on heart rate variability.

BACKGROUND: Impaired cardiac autonomic function may contribute to the risk of sudden unexpected death in epilepsy (SUDEP). Clinical observations indicate that successful epilepsy surgery is associated with a reduced risk of SUDEP. However, in a previous study we found impaired cardiac control pre-surgically in patients with poor outcome of surgery, indicating an a priori lower risk in responders to epilepsy surgery. We have now examined the effect of surgery on cardiac autonomic control in the same patients. METHODS: We used 24 h EKG recordings to assess heart rate variability (HRV) by spectral analysis in 21 consecutive patients after temporal lobe epilepsy surgery. The HRV was compared with healthy controls, with pre-surgical HRV in the same patients, and analyzed in relation to seizure control 1 year after surgery. RESULTS: The patients with poor outcome after surgery had significantly lower SD of RR-intervals, total power, very low frequency power and low frequency power than matched healthy controls. The patients with favorable outcome did not differ from the controls, and the postoperative HRV was not different from HRV before surgery in any of the patient groups. CONCLUSION: We could not demonstrate any effect on HRV of temporal lobe epilepsy surgery in these patients. The observed lower HRV in the poor outcome group was present already before epilepsy surgery as previously reported. Although our results need confirmation in a larger study, the observations suggest that the increased risk of SUDEP in patients failing epilepsy surgery may be due to a common factor predisposing to surgical failure, impaired HRV as well as to an increased risk of SUDEP.

Decreased cortical levels of astrocytic glutamate transport protein GLT-1 in a rat model of posttraumatic epilepsy.

The extracellular homeostasis of glutamate in the brain is maintained by the efficient uptake into astroglial cells. The high extracellular glutamate levels seen during seizures are therefore probably a result of both an increased synaptic release and a deranged glutamate uptake. In this study we used immuno-blotting technique to measure the cortical levels of the astrocytic glutamate transport protein (GLT-1) and of the glutamate and aspartate transporting protein (GLAST) in an epilepsy model induced by ferrous chloride injection in the cortex of rats. The levels of GLT-1 were lower in epileptic rats than in controls, day 1 and 5 after induction, but not at 3 months. Glial fibrillary protein (GFAP) levels increased with time in the epileptic model, whereas GLAST and beta-tubulin III remained unchanged compared to controls. The results suggest that the transient decrease of GLT-1 could play a role in epileptogenesis, while recurrent seizure activity may be maintained by other mechanisms.

Platelet and brain GABA-transaminase and monoamine oxidase activities in patients with complex partial seizures.

UNLABELLED: The activities of gamma-aminobutyrate aminotransferase (GABA-T) and monoamine oxidase (MAO-A and -B) were measured in blood platelets from 27 patients and hippocampal tissues from eight (GABA-T) and ten (MAO) patients with complex partial seizures. The activity of platelet GABA-T was found to be higher in the epileptic patients (43.37 +/- 13.53 pmol/min/mg protein, P < 0.005) in comparison with that found in 14 healthy volunteer subjects (29.59 +/- 13.14 pmol/min/mg protein). This difference was most pronounced in patients treated with carbamazepine (CBZ) (P < 0.01) and phenytoin (PHT) (P < 0.01). Contrary to the platelets, the activity of GABA-T in the hippocampi from the epileptic patients (6.937 +/- 2.204 nmol/min/mg protein) did not differ significantly from that found in seven non-epileptic control cases (7.158 +/- 0.951 nmol/min/mg protein). The increase in GABA-T activity in the blood platelets from the epileptic patients could not be explained by a direct effect of the antiepileptic compounds, since there were no changes in the activities on exposure to PHT, CBZ or VPA in vitro, either of blood platelets or of brain tissue. With regard to platelet MAO, no difference in the activity was found between the two groups, whereas the MAO-B activity in the hippocampi was significantly higher in the epileptic patients (3.51 +/- 1.32 nmol/mg/mg protein) than in the control cases (1.21 +/- 0.73 nmol/mg/mg protein) (P < 0.0004). There was no difference in MAO-A activity in the hippocampi between epileptic patients and controls. CONCLUSION: In the hippocampi from patients with complex partial seizures the activities of the mitochondrial enzymes GABA-T and MAO-A were similar to those found in control subjects. The activity of MAO-B, however, was significantly higher indicating that there is an increased proportion of reactive astrocytes in epileptic hippocampus.

Preoperative heart rate variability in relation to surgery outcome in refractory epilepsy.

BACKGROUND: Epilepsy patients may have an impaired autonomic cardiac control, which has been associated with an increased incidence of sudden unexpected death among people with epilepsy (SUDEP). The risk of SUDEP is particularly high among epilepsy surgery candidates with refractory epilepsy. This risk seems to be reduced after successful surgery but whether this is an effect of surgery or reflects pre-existing differences between good and poor responders is under debate. METHODS: We used spectral analysis to analyze prospectively heart rate variability (HRV) preoperatively in 21 consecutive patients with temporal lobe epilepsy who were planned for epilepsy surgery. The presurgical HRV based on ambulatory 24 hours EKG recordings was analyzed in relation to seizure control at 1 year after surgery. RESULTS: Patients had significantly lower SD of RR-intervals, total power, very low frequency power and low frequency power than matched healthy controls. Patients with good outcome of surgery (Engel class I; n = 11) did not differ from their controls while those with poor outcome (Engel class II-IV; n = 10) had significantly lower power in all domains than those with a favorable outcome. CONCLUSIONS: Measurements of heart rate variability preoperatively indicate that patients with a poor outcome of surgery have a more pronounced impairment of sympathetic as well as parasympathetic cardiac control than those with good outcome. Reduced heart rate variability may be associated with an increased risk of sudden unexpected death among people with epilepsy (SUDEP). Good surgery candidates may a priori have a lower risk of SUDEP.

[Diagnosis of epilepsy by PET scan]. / Epilepsidiagnostik med PET.

Neuroimaging techniques have a great impact on the evaluation and treatment of patients with epilepsy. Positron emission tomographic studies with 18F-FDG can provide valuable data for presurgical localization of epileptogenic zones. There are also a number of receptor ligands for PET studies available, including benzodiazepine, opiate and cholinergic tracers. Ligands for monoamine oxidase B and glutamate receptors are being developed.

In vitro quantitative autoradiography of [3H]-L-deprenyl and [3H]-PK 11195 binding sites in human epileptic hippocampus.

Distribution of the enzyme monoamine oxidase B (MAO-B) and the peripheral benzodiazepine binding site (omega 3 site) was studied by quantitative autoradiography using [3H]L-deprenyl and [3H]PK 11195, two tentative glial markers, as ligands. Sclerotic hippocampus from seven patients who had had anterotemporal lobe resection because of intractable complex partial epilepsy were investigated and compared with postmortem hippocampus from three nonepileptic controls. A significantly higher degree of L-deprenyl and PK 11195 binding was observed in the epileptic cases. The increased binding of both ligands correlated to extent of neuronal loss, but only PK 11195 showed correlation to degree of gliosis. We concluded that both ligands could provide useful markers for quantitating the degree of gliosis in pathologic states such as epilepsy. They may be applicable in future in vivo studies with positron emission tomography (PET).

NMDA-receptor activity visualized with (S)-[N-methyl-11C]ketamine and positron emission tomography in patients with medial temporal lobe epilepsy.

PURPOSE: To determine whether neurochemical activation of the N-methyl-D-aspartate (NMDA) receptor-gated ion channel shows quantitative changes, measured as binding of 11C-labeled (S)-[N-methyl]ketamine, in patients with medial temporal lobe epilepsy (MTLE). METHODS: Eight patients with MTLE who were evaluated regarding epilepsy surgery underwent positron emission tomography (PET) with (S)-[N-methyl-11C]ketamine. The presurgical investigations included magnetic resonance imaging (MRI), PET with 18F-fluoro-deoxyglucose (18FDG), and seizure monitoring by using video-EEG. The uptake of (S)-[N-methyl-11C]ketamine in the temporal lobe of ictal onset was compared with the contralateral side and correlated to changes in regional glucose metabolism measured by PET with 18FDG. RESULTS: (S)-[N-methyl-11C]ketamine rapidly reached the brain, and high radioactivities were measured in the striatum, thalamic nuclei, and cortical regions. Overall the brain uptake and regional binding potentials of (S)-[N-methyl-11C]ketamine were similar to measurements observed previously in healthy controls. However, 20 min after administration, when blood flow influence was negligible, a side-to-side comparison revealed a 9-34% reduction of tracer radioactivity in the temporal lobes of ictal onset. At earlier times, the differences in binding potentials were less pronounced, 9-21%. The magnitude and distribution of the reduction were similar to the metabolic pattern seen on PET scans with 18FDG. CONCLUSIONS: Radioactivity uptake of intravenously administered (S)-[N-methyl-11C]ketamine was reduced in temporal lobes of ictal in patients with TLE. This may reflect reduced NMDA-receptor density, reduced perfusion, focal atrophy, or other factors.

Temporal lobe epilepsy visualized with PET with 11C-L-deuterium-deprenyl--analysis of kinetic data.

OBJECTIVES: The purpose of the study was to develop a simplified method for the acquisition and analysis of data from positron emission tomography (PET) using the ligand 11C-L-deuterium-deprenyl. This is motivated by an increased interest in methods to characterize gliosis in neurodegenerative diseases and epilepsy, which can be defined due to an increased expression of the enzyme MAO-B. METHODS: Seven patients with temporal lobe epilepsy were investigated with PET. The tracer kinetics in different brain structures was recorded and analyzed using different models with and without a plasma input function. The derived values were correlated to literature values of 3H-deprenyl binding in frozen sections from normal human brains. RESULTS: A good correlation was seen between in vivo binding and in vitro data, with the correlation being equally good irrespective of whether metabolite corrected plasma or modified cerebellar uptake values were used as input function. The epileptic lobe was, compared to non-epileptic, characterized by a lower initial distribution and an enhanced late accumulation of the tracer. With the applied method, it was possible to correctly identify the epileptic side in all 6 unilateral patients and I probable bilateral case. CONCLUSIONS: PET with 11C-L-deuterium-deprenyl gives a good correlation between calculated in vivo binding and MAO-B activity. The analysis can be simplified and blood sampling avoided if modified cerebellar time-activity data is used as a reference. Separate images of distribution volume and MAO-B binding can be generated.

Health-related quality of life after epilepsy surgery: a Swedish multicenter study.

PURPOSE: To investigate health-related quality of life (HRQOL) in relation to seizure outcome as part of a multicenter follow-up of epilepsy surgery in Sweden. METHODS: A battery including the SF-36 Health Survey and the Hospital Anxiety and Depression scale (HAD) was distributed to all patients older than 16 years. Mean follow-up time was 4 years (range, 2-13 years) and response rate, 91% (103 of 113 patients). HRQOL data were related to seizure frequency and severity (Chalfont Seizure Severity Scale). RESULTS: Seventy-six percent considered their global health to be better than it was before surgery. Degree of improvement in seizure control correlated with improved satisfaction with health (Spearman's r = 0.44). Higher SF-36 scores (higher HRQOL ratings) correlated with percentage reduction of seizure frequency for all scales and was strongest for perception of general health (Spearman's r = 0.46). When the patients were divided into four categories [A, completely seizure free (n = 29); B, seizure free with aura (n = 18); C, > or =75% reduction in seizure frequency (n = 24); and D, <75% reduction in seizure frequency (n = 32)], a strong positive association was found between higher SF-36 scores (with the exception of physical functioning) and better seizure control. Health-related limitations in role performance differentiated best between the outcome categories. For patients with > or =75% reduction in seizure frequency, low seizure severity correlated with higher HRQOL ratings for scales measuring social function, vitality, and mental health. Depression levels (HAD scale scores) were on average low. Anxiety (HAD) increased significantly from A to D. CONCLUSIONS: HRQOL seems to be scored as a continuum in relation to seizure frequency. Seizure severity measures give complementary information.

PET with 11C-deuterium-deprenyl and 18F-FDG in focal epilepsy.

OBJECTIVES: This study compares positron emission tomography (PET) using 11C-deuterium-deprenyl (DED) with PET using 18F-fluorodeoxyglucose(18F-FDG) for examining epileptogenic regions in patients with focal epilepsy. MATERIAL AND METHODS: Twenty-three patients undergoing evaluation for epilepsy surgery were subjected to PET with DED. Fourteen patients had mesial temporal lobe epilepsy (TLE) and 9 patients had seizures of neocortical origin. In addition, 6 healthy control subjects were examined. Pixel-by-pixel analysis was used to generate graphical images of tracer distribution volume (intercept) and the accumulation rate (slope). Asymmetries with respect to relative intercept and slope were compared in patients with temporal lobe epilepsy (TLE), in patients with extra-temporal lobe epilepsy (exTLE), and in the control subjects. The results were compared with 18F-FDG-PET. RESULTS: Among the patients with TLE, significant differences between the epileptogenic and the contralateral lobe were found with DED intercept and FDG-uptake. No significant differences were found with DED slope. The exTLE and the control groups showed no significant differences between sides or lobes. CONCLUSIONS: This study indicates that PET with 11C-deuterium-deprenyl is a useful method for identifying TLE and is equivalent to PET with 18F-FDG in this sense. The method has little localizing value in seizures originating from neocortical structures.

Positron emission tomography with [11C]deuterium-deprenyl in temporal lobe epilepsy.

We performed positron emission tomography (PET) with [11C]deuterium-deprenyl in 9 patients with temporal lobe epilepsy (TLE) undergoing evaluation for possible epilepsy surgery. Seven patients had unilateral and 2 had bilateral mesiotemporal epileptic foci based on the preoperative investigation including ictal EEG discharges and PET with 2-[18F]fluoro-2-deoxyglucose (FDG). Deprenyl is an irreversible inhibitor of monoamine oxidase type B (MAO-B) with a very high affinity for the enzyme. In the brain, MAO-B is preferentially located in astrocytes, and a previous in vitro study showed increased binding of the ligand in sclerotic hippocampi. Dynamically acquired N-[methyl-11C]-a,a-di-deutero-L-deprenyl distribution in PET images were analyzed graphically, and the focus regions were assessed visually on the PET images. In addition, the accumulation rate and distribution volume of the tracer relative to the cerebellar cortex were measured in standardized homologous temporal regions by semiquantitative methods. Uptake of [11C]deuterium-deprenyl was significantly increased in the epileptogenic temporal lobes, both apparently and semiquantitatively. By calculating mean interlobar ratios, we identified the temporal lobe containing the epileptic focus in six unilateral cases. One case was ambiguous but was not falsely localized. The two bilateral cases were correctly identified as such. Our results suggest that PET with [11C]deuterium-deprenyl might be a useful method for identification of epileptogenic temporal lobes.