The relevance of neuropsychiatric symptoms and cognitive problems in new-onset epilepsy - Current knowledge and understanding.

Neurobehavioral and cognition problems are highly prevalent in epilepsy, but most research studies to date have not adequately addressed the precise nature of the relationship between these comorbidities and seizures. To address this complex issue and to facilitate collaborative, innovative research in the rising field of neurobehavioral comorbidities and cognition disturbances in new-onset epilepsy, international epilepsy experts met at the 3rd Halifax International Epilepsy Conference & Retreat at White Point, South Shore, Nova Scotia, Canada from September 18 to 20, 2014. This Conference Proceedings provides a summary of the conference proceedings. Specifically, the following topics are discussed: (i) role of comorbidities in epilepsy diagnosis and management, (ii) role of antiepileptic medications in understanding the relationship between epilepsy and neurobehavioral and cognition problems, and (iii) animal data and diagnostic approaches. Evidence to date, though limited, strongly suggests a bidirectional relationship between epilepsy and cognitive and psychiatric comorbidities. In fact, it is likely that seizures and neurobehavioral problems represent different symptoms of a common etiology or network-wide disturbance. As a reflection of this shared network, psychiatric comorbidities and/or cognition problems may actually precede the seizure occurrence and likely get often missed if not screened.

Angioarchitecture of brain AVM determines the presentation with seizures: proposed scoring system.

BACKGROUND AND PURPOSE: Seizures are a common presentation in patients with brain arteriovenous malformations, but the pathogenesis of seizures remains poorly understood. The purpose of our study was to analyze various morphologic and hemodynamic characteristics of unruptured BAVMs presenting primarily with seizures and, on the basis of these, to propose a scoring system to predict seizures in patients with BAVMs. MATERIALS AND METHODS: In a retrospective review of our BAVM data base from 2000 to 2009, after excluding patients with ruptured BAVMs, we classified patients into 2 groups, those with and without seizures at presentation. Clinical, angiographic, and hemodynamic characteristics on cerebral angiograms of all these patients were studied. The association between various angioarchitectural variables and seizure presentation was examined, and these results were used to guide the development of criteria to predict presentation with seizures. RESULTS: Of 1299 patients in our data base, we finally analyzed 33 patients with unruptured BAVMs with seizures and 45 patients with unruptured AVMs without seizures. Location, fistulous component in the nidus, venous outflow stenosis, and the presence of a long pial course of the draining vein were identified as the strongest predictors of seizures. The proposed scoring system had good predictability of presentation with seizures. CONCLUSIONS: Specific angioarchitectural characteristics of unruptured BAVMs may predict occurrence of seizures and may help in targeted treatment.

Postoperative memory prediction in left temporal lobe epilepsy: the Wada test is of no added value to preoperative neuropsychological assessment and MRI.

The contribution of the Wada test (intracarotid amytal procedure, IAP) to predicting postoperative memory outcome in left temporal lobe epilepsy (LTLE) is becoming increasingly controversial when preoperative neuropsychological evaluation and MRI findings are available. We retrospectively analyzed 59 patients with LTLE who underwent en bloc temporal lobe resection. All patients had valid bilateral IAP test results, complete pre- and postoperative neuropsychological evaluation, and MRI grading on a 5-point scale integrating T 2 signal increase and degree of atrophy. Thirty percent of patients showed postoperative memory decline. Multiple regression analysis revealed that significant predictors of decline [F(2.56)=22.71, P<0.001, r(2)=0.448] included preoperative memory learning score [t=-5.89, P<0.001] and MRI classification [t=3.10, P<0.003], but not IAP scores. The IAP is of no added value in the prediction of postoperative memory outcome in LTLE in the presence of comprehensive neuropsychological and MRI data.

[Therapeutic drug monitoring in epileptology and psychiatry]. / "Therapeutic drug monitoring" in Epileptologie und Psychiatrie.

Experts from epileptology and psychiatry reviewed the current significance of therapeutic drug monitoring (TDM) of antiepileptic drugs and psychiatric drugs in a workshop at Bethel Epilepsy Centre in December 2005. TDM has been essential in epileptology for about 30 years, and it is also increasingly important in psychiatry, in which consensus recommendations were published recently. With regard to cost-cutting in the health system, there are discussions about the financial effect of TDM and outsourcing it to bigger laboratories. In psychiatry it has however been shown that sensibly used TDM may lead to reduced costs. Many issues in TDM require the knowledge and experience of specialised laboratories. The use of TDM data for scientific purposes was discussed at the workshop as well.

The contribution of 18F-FDG PET in preoperative epilepsy surgery evaluation for patients with temporal lobe epilepsy A meta-analysis.

OBJECTIVE: To assess the predictive diagnostic added value of positron emission tomography (PET) in preoperative epilepsy surgery evaluation for patients with temporal lobe epilepsy (TLE). METHODS: A meta-analysis of publications from 1992 to 2006 was performed. Forty-six studies were identified that met inclusion criteria presenting detailed diagnostic test results and a classified postoperative outcome. Studies exclusively reporting on patients with brain tumors or on children were excluded. RESULTS: The analyses were complicated by significant differences in study design and often by lack of precise patient data. Ipsilateral PET hypometabolism showed a predictive value of 86% for good outcome. The predictive value was 80% in patients with normal MRI and 72% in patients with non-localized ictal scalp EEG. In a selected population of 153 TLE patients with a follow-up of >12 months PET correlated well with other non-invasive diagnostic tests, but none of the odds ratios of any test combination was significant. CONCLUSION: Our data confirm that ipsilateral PET hypometabolism may be an indicator for good postoperative outcome in presurgical evaluation of drug-resistant TLE, although the actual diagnostic added value remained questionable and unclear. PET does not appear to add value in patients localized by ictal scalp EEG and MRI. Prospective studies limited to non-localized ictal scalp EEG or MRI-negative patients are required for validation.

[Management of refractory status epilepticus from a neurologic and neuropediatric perspective]. / Management des refraktären Status epilepticus: Eine Bestandsaufnahme aus neurologischer und neuropädiatrischer Sicht.

Status epilepticus is a frequent neurologic emergency that is refractory to benzodiazepines and phenytoin in 60% to 70% of cases. Patients commonly require management in an intensive care unit incorporating aggressive treatment with intravenous anaesthetics. Treatment guidelines commonly comment on initial pharmacologic management in detail, as they can refer to data from randomised controlled trials. In contrast, recommendations for the management of refractory status epilepticus often are sparse, as they rely on data from retrospective or uncontrolled prospective studies only. Since status epilepticus is refractory in every third patient, a critical analysis of the available data and a review focussing on the further management of this condition are urgently needed. The Koenigstein Team, a panel of expert epileptologists and neuropediatricians, discussed at its 31(st) meeting in March 2006 the clinical and experimental aspects and implicit prognostic variables of refractory status epilepticus. Here we present the results of that discussion and state recommendations from a neurologic and neuropediatric perspective for current und future management of refractory status epilepticus.

The role of 1H magnetic resonance spectroscopy in pre-operative evaluation for epilepsy surgery. A meta-analysis.

PURPOSE: We aimed to assess the additional pre-operative value of (1)H MRS in identifying the epileptogenic zone (EZ) for epilepsy surgery by performing a meta-analysis considering publications from 1992 to 2003. METHODS: From an extensive computer and hand search 22 studies were included. For inclusion, studies had to report post-operative outcome and detailed diagnostic test results for each individual patient. Studies exclusively reporting on patients with brain tumors or on children were excluded. RESULTS: Great heterogeneity among studies regarding methodological and technical aspects and concerning evaluation and interpretation of data was observed. Only patients with intractable temporal lobe epilepsy were presented. Sixty-four percent of all patients and 72% of patients with good outcome had an ipsilateral MRS abnormality concordant with the EZ. The positive predictive value of all patients with ipsilateral MRS abnormality for good outcome was 82%. An odds ratio weighted by inverse variance showed a 4.891 better chance of seizure free outcome [CI=1.965-12.172; Q=2.748; d.f.=5; critical chi2-value=11.07] in patients with an ipsilateral MRS abnormality when compared to patients with bilateral MRS abnormalities. Data for MRI-negative patients were conflicting. One study stressed a role for MRS in patients with bilateral hippocampal atrophy at MRI. CONCLUSIONS: MRS still remains a research tool with clinical potential. Our findings indicate the connection of ipsilateral MRS abnormality to good outcome. The ability for prediction of post-operative outcome may depend on the assessed population. Prospective studies limited to non-localized ictal scalp EEG or MRI-negative patients are required for validation of these data.

Transient lesion in the splenium of the corpus callosum and antiepileptic drug withdrawal.

OBJECTIVE: To test pathophysiologic hypotheses regarding the occurrence of a splenial lesion in patients with epilepsy. METHODS: The authors studied 16 patients with a splenial lesion and 32 control patients, all of whom had MRI examination immediately after presurgical EEG long-term monitoring (LTM). The authors compared the number of generalized tonic-clonic and partial seizures during LTM, antiepileptic drug (AED) withdrawal, and laboratory results. RESULTS: All of the patients with a splenial lesion had their AEDs stopped completely, vs 47% of the controls (p = 0.001). Patients with SCC lesion had a longer duration of complete withdrawal (median 3.5 vs 2 days, p = 0.03). There was no correlation with seizure frequency or the introduction of new AEDs. CONCLUSION: A lesion of the splenium of the corpus callosum in patients with epilepsy is not associated with toxic drug effects or high seizure frequency, but might be induced by a rapid and relatively long-lasting reduction of antiepileptic drugs. Its frequency might be underestimated as MRI after long-term monitoring is rarely done.

Issues when treating epilepsy in the elderly.

Single seizures and epilepsy are one of the most commonly encountered neurologic disorders in elderly individuals, arising as a result of complex and often multiple acquired underlying pathologies. Ischemia is by far the most frequent etiology, and is found in up to one-third of these patients, followed by tumors, which are diagnosed in approximately 10% of affected individuals. Thus, a multidisciplinary approach to its diagnosis and management is required. Antiepileptic drug (AED) therapy is the mainstay of treatment for epilepsy in the elderly, but age-specific changes in drug metabolism, increased sensitivity to side effects, and the risk of drug interactions must be considered. Some newer AEDs seem to offer advantages over the older agents in terms of their reduced drug interaction potential (due to lack of enzyme induction), and improved tolerability profiles, which is supported by few recent clinical trials. In order to achieve seizure freedom without causing intolerable side effects, treatment should be initiated with monotherapy at low doses and titrated slowly to within the recommended dose range.

Epileptic activity influences the lateralization of mesiotemporal fMRI activity.

OBJECTIVE: To identify clinical factors contributing to the lateralization of mesiotemporal memory functions in epilepsy by using memory-activated fMRI. METHODS: Sixty patients aged 16 to 63 years with mesial temporal lobe epilepsy (MTLE) and 20 patients aged 16 to 60 years with extratemporal epilepsy (ETE) due to circumscribed epileptogenic lesions who consecutively underwent presurgical evaluation including continuous video-EEG monitoring and structural MRI examinations were examined. During memory fMRI, the activation condition consisted of retrieval from long-term memory induced by self-paced performance of an imaginative walk through the patient's hometown. On the basis of a previous study, memory lateralization was defined as typical if larger fMRI activation was in the mesiotemporal structures contralateral to the epileptic focus. RESULTS: There were 45 patients with MTLE who had typical memory lateralization (75%), whereas only 9 patients (45%) with ETE exhibited typical memory lateralization (p = 0.013). In MTLE patients, bilateral independent epileptiform discharges occurred more often in the atypical group than in patients with typical memory lateralization (p = 0.015). CONCLUSIONS: The fMRI lateralization of mesiotemporal visuospatial memory functions in patients with mesiotemporal lobe epilepsy (MTLE) is asymmetric: The larger activation usually appears contralateral to the side of the epileptogenic region. These findings occur more often in MTLE; in patients with extratemporal epilepsy, such type of asymmetry is not characteristic. In MTLE patients with bilateral independent epileptiform discharges, this type of asymmetry is also less frequent.

Evolution of MRI changes and development of bilateral hippocampal sclerosis during long lasting generalised status epilepticus.

This report describes a previously healthy 28 year old patient with a 5 month period of intractable generalised status epilepticus (SE) of unknown aetiology with fatal outcome. Repeated magnetic resonance imaging (MRI) showed no pre-existing abnormality, but did show progressive cortical and hippocampal atrophy and T2 hyperintensity in both hippocampal formations, suggestive of progressive tissue damage. Post-mortem histopathological analysis revealed substantial neuronal cell loss including CA1 and CA4 sectors of the hippocampus compatible with bilateral hippocampal sclerosis. There was no evidence of systemic complications including arterial hypotension and hypoxia, hypoglycaemia, hyperpyrexia, or other confounding factors to account for these findings. This case provides further evidence of SE induced hippocampal damage in humans.

Value of the early electroencephalogram after a first unprovoked seizure.

Studies on the predictive value of the electroencephalogram (EEG) concerning the risk of seizure recurrence have shown contradictory results. We prospectively studied the predictive value of the standard EEG and EEG with sleep deprivation for seizure relapse in adult patients presenting with a first unprovoked seizure. EEGs were performed on 157 adult patients within the first 48 hours of the first seizure. Additional EEGs with sleep deprivation were obtained in 60 cases. The standard EEG was abnormal in 70.7% and significantly associated with an increased risk of seizure recurrence [risk ratio 4.5, 95% confidence interval (CI) 1.8; 11.3, p=0.001]. Subgroup analysis revealed the highest recurrence rates for patients with focal epileptiform activity (risk ratio 2.2, CI 1.2; 4.2, p=0.01). EEGs with sleep deprivation were abnormal in 48.3% of all cases and revealed epileptiform discharges in 13.3% of the patients who had no epileptiform activity in the standard EEG. Routine EEG revealed abnormalities in 60 of 94 patients who presented with normal neurologic status on admission. Further neuroradiological examinations detected previously unknown brain lesions in 19 of these cases, particularly cerebrovascular disease (CVD, n=7), brain tumors (n=6), and posttraumatic scars (n=4). In conclusion, the EEG is important for the early detection of focal nonepileptic and epileptic abnormalities after a first unprovoked seizure in adult patients and may provide valuable information on previously unknown disorders, particularly CVD and cerebral tumors. The abnormal EEG is a highly significant predictor for seizure recurrence. An additional EEG with sleep deprivation is helpful in cases when standard EEG does not reveal epileptiform discharges.

Valproate induces reversible factor XIII deficiency with risk of perioperative bleeding.

The antiepileptic drug valproic acid (VPA) induces subclinical changes in both the intrinsic and extrinsic coagulation system. However, fatal bleeding is very rare. This study reports a 39-year-old patient who underwent selective amygdalohippocampectomy because of drug-resistant temporal lobe epilepsy. Preoperatively, the patient was on a combined therapy with VPA and topiramate, and routine coagulation laboratory parameters were entirely normal. Epilepsy surgery was immediately followed by severe intracranial bleeding events which promped repeated craniectomy. Extensive laboratory analyses revealed a factor XIII activity level of 17%, indicating factor XIII deficiency confirmed by a reduced XIIIA-antigen. After termination of treatment with VPA, factor XIII levels returned to normal. Control examinations after 9 and 24 months showed normal range values for all coagulation parameters, including factor XIII, platelet function, and von Willebrand factor. To our knowledge, this case is the first description of a well-documented, clinically relevant transient factor XIII-deficiency syndrome related to VPA treatment.

[The epilepsypsychoses]. / Die Epilepsiepsychosen.

The association of epilepsy, the epilepsypsychoses and schizophrenia has attracted the attention of psychiatrists and neurologists since the nineteenth century. While until the 1970ies German speaking psychiatry had shown great interest, in recent years there have been only a small number of publications on this topic. However there has been intensive research likewise on the epilepsypsychoses, especially on the association of temporal lobe epilepsy and schizophrenia in the English-speaking psychiatry. The epilepsypsychoses are inadequately categorized by the modern classification systems. Current knowledge of either the epilepsypsychoses or the relationship between epilepsy and schizophrenia is examined.

Dose-response effect of levetiracetam 1000 and 2000 mg/day in partial epilepsy.

PURPOSE: To evaluate the efficacy, dose-response, tolerability, and withdrawal effects of levetiracetam (Keppra) as adjunctive therapy in adult patients with partial epilepsy. METHODS: In this European multicenter, double-blind, randomized, cross-over trial, levetiracetam 1000 or 2000 mg/day given in two divided doses was compared to placebo as add-on therapy in 324 patients with refractory partial seizures with or without secondary generalization. This trial consisted of six periods: an 8- or 12-week baseline, a treatment period A (4-week titration and 12-week evaluation), a treatment period B (4-week titration and 12-week evaluation), and a withdrawal period. During each evaluation period (A and B), patients received two of the three possible treatment regimens. RESULTS: This study provides additional information on dose-response effects and withdrawal phenomena and confirms the responder and seizure freedom rates previously reported in the parallel part of the study (Epilepsia 41 (2000) 1179-1186). Both doses of levetiracetam significantly decreased mean partial seizure frequency compared with placebo (P<0.001), and significantly more patients receiving levetiracetam had > or = 50 and > or = 75% reductions in partial seizure frequency (1000 mg, P=0.004 and P=0.043, respectively; 2000 mg P=0.001 and P<0.001, respectively). In addition, 5.5% (10/183) of patients receiving levetiracetam 1000 mg/day and 6.3% (11/175) of patients receiving levetiracetam 2000 mg/day were seizure-free during the corresponding evaluation period, compared with 1.2% (2/172) of patients on placebo. A within-patient comparison revealed a significantly greater responder rate for the higher levetiracetam dose (P=0.018). The most commonly reported adverse effects (> or = 5% and more frequent in one of the groups with levetiracetam) were headache, asthenia, infection, somnolence, pharyngitis, dizziness, and pain. No withdrawal-related adverse events were reported during the cross-titration period. CONCLUSIONS: Levetiracetam was effective and well-tolerated and decreased seizure frequency in a dose-dependent manner, with no evidence of typical withdrawal-related adverse events or rebound phenomena after withdrawal or down-titration.

[Reversible phenytoin-induced extrapontine myelinolysis]. / Reversible Phenytoininduzierte extrapontine Myelinolyse.

Antiepileptic drug (AED)-induced side effects still may hinder antiepileptic therapy. We describe a 38-year-old woman with complex focal seizures. Due to normal neuroradiological findings and the lack of evident pathogenetic factors, we diagnosed cryptogenic epilepsy. In response to cognitive side effects, the initial therapy with phenobarbital was replaced by phenytoin treatment only. Subsequent MRI investigation showed a hyperintense lesion in the corpus callosum without gadolinium enhancement. Responding to an increase in seizure frequency (SF), phenytoin was replaced first by lamotrigin monotherapy and then by additional valproate treatment. An MRI follow-up investigation did not show the previously described lesion of the corpus callosum, thus suggesting phenytoin-induced extrapontine myelinolysis. In the literature, vigabatrin-induced demyelinization of the corpus callosum has also been described. In patients treated with the AEDs phenytoin or vigabatrin who demonstrate increased SF, such a side effect should be taken into account and MRI investigation performed.

Functional recovery despite prolonged bilateral loss of somatosensory evoked potentials: report on two patients.

A bilateral loss of short latency somatosensory evoked potentials (SSEPs) after head trauma or non-traumatic brain damage is normally associated with a deleterious neurological outcome. An adequate recovery in reported in two deeply comatose patients with head trauma or severe hypertensive encephalopathy despite prolonged bilateral loss of SSEPs over days, found in repeated recordings. Hence, a bilateral loss of SSEPs should not be considered alone for prediction of outcome in cerebral injury.

[Transverse myelopathy as a complication following long-term intrathecal application of morphine in chronic back pain]. / Querschnittsmyelopathie als Komplikation einer intrathekalen Langzeitapplikation von Morphium bei chronischen Rückenschmerzen.

Serious neurological complications following long-term intrathecal application of opiates have seldom been published. This report describes complications which developed three months after reimplantation of a spinal catheter for pain therapy. The symptoms which occurred were paraparesis of the legs with sensory loss and urinary retention. A regression of these symptoms occurred only after explantation of the spinal catheter-pump-system. Possible reasons and consequences are discussed.