Histopathological Findings in Brain Tissue Obtained during Epilepsy Surgery.

BACKGROUND: Detailed neuropathological information on the structural brain lesions underlying seizures is valuable for understanding drug-resistant focal epilepsy. METHODS: We report the diagnoses made on the basis of resected brain specimens from 9523 patients who underwent epilepsy surgery for drug-resistant seizures in 36 centers from 12 European countries over 25 years. Histopathological diagnoses were determined through examination of the specimens in local hospitals (41%) or at the German Neuropathology Reference Center for Epilepsy Surgery (59%). RESULTS: The onset of seizures occurred before 18 years of age in 75.9% of patients overall, and 72.5% of the patients underwent surgery as adults. The mean duration of epilepsy before surgical resection was 20.1 years among adults and 5.3 years among children. The temporal lobe was involved in 71.9% of operations. There were 36 histopathological diagnoses in seven major disease categories. The most common categories were hippocampal sclerosis, found in 36.4% of the patients (88.7% of cases were in adults), tumors (mainly ganglioglioma) in 23.6%, and malformations of cortical development in 19.8% (focal cortical dysplasia was the most common type, 52.7% of cases of which were in children). No histopathological diagnosis could be established for 7.7% of the patients. CONCLUSIONS: In patients with drug-resistant focal epilepsy requiring surgery, hippocampal sclerosis was the most common histopathological diagnosis among adults, and focal cortical dysplasia was the most common diagnosis among children. Tumors were the second most common lesion in both groups. (Funded by the European Union and others.).

Prevalence and outcome of late-onset seizures due to autoimmune etiology: A prospective observational population-based cohort study.

OBJECTIVE: The increasing incidence of new-onset seizures with age is well known. Often, the etiology cannot be clarified. In the present study, patients with unprovoked late-onset seizures and without known neoplasm, who might have had paraneoplastic encephalitis, were investigated for a potentially underlying autoimmunity. METHODS: Sixty-six consecutive patients (36 women; aged ≥55 years) after having at least one seizure or seizures for ≤6 months were prospectively identified over a period of 4.75 years. All patients were tested for serum and cerebrospinal fluid (CSF) antibodies (Abs) to both neural cell-surface and intracellular antigens. Forty-five (68%) underwent brain magnetic resonance imaging (MRI). Follow-up in Ab-positive cases was ≥6 months. RESULTS: Two patients had high titers of anti-CASPR2 (contactin-associated protein-like 2) Abs in serum and CSF and fulfilled the diagnostic criteria of definite limbic encephalitis. Another two patients had bilateral encephalitic temporal MRI abnormalities. They also satisfied the criteria of definite limbic encephalitis, even though they had no Abs in serum or CSF. All four were in the age range of 55-70 years. They received immunotherapy and/or antiepileptic drug treatment and became seizure-free. SIGNIFICANCE: Our findings suggest that autoimmunity should be considered an important etiology in patients with late-onset seizures. Testing for neural antibodies and brain MRI may be worthwhile in this patient group.

Postmarketing experience with brivaracetam in the treatment of epilepsies: A multicenter cohort study from Germany.

OBJECTIVE: To evaluate factors predicting efficacy, retention, and tolerability of add-on brivaracetam (BRV) in clinical practice. METHODS: A multicenter, retrospective cohort study recruiting all patients who started BRV between February and November 2016 with observation time between 3 and 12 months. RESULTS: Of a total of 262 patients (mean age 40, range 5-81 years, 129 male) treated with BRV, 227 (87%) were diagnosed to have focal, 19 (7%) idiopathic generalized and 8 (3%) symptomatic generalized epilepsy, whereas 8 (3%) were unclassified. The length of exposure to BRV ranged from 1 day to 12 months, with a median retention time of 6.1 months, resulting in a total exposure time to BRV of 1,504 months. The retention rate was 79.4% at 3 months and 75.8% at 6 months. Efficacy at 3 months was 41.2% (50% responder rate) with 14.9% seizure-free for 3 months and, at 6 months, 40.5% with 15.3% seizure-free. Treatment-emergent adverse events were observed in 37.8% of the patients, with the most common being somnolence, dizziness, and behavioral adverse events (BAEs). BAE that presented under previous levetiracetam (LEV) treatment improved upon switch to BRV in 57.1% (20/35) and LEV-induced somnolence improved in 70.8% (17/24). Patients with BAE on LEV were more likely to develop BAE on BRV (odds ratio [OR] 3.48, 95% confidence interval [CI] 1.53-7.95). SIGNIFICANCE: BRV in broad clinical postmarketing use is a well-tolerated anticonvulsant drug with 50% responder rates, similar to those observed in the regulatory trials, even though 90% of the patients included had previously been exposed to LEV. An immediate switch from LEV to BRV at a ratio of 10:1 to 15:1 is feasible. The only independent significant predictor of efficacy was the start of BRV in patients not currently taking LEV. The occurrence of BAE during previous LEV exposure predicted poor psychobehavioral tolerability of BRV treatment. A switch to BRV can be considered in patients with LEV-induced BAE.

Costs and cost-driving factors for acute treatment of adults with status epilepticus: A multicenter cohort study from Germany.

OBJECTIVE: To provide first data on inpatient costs and cost-driving factors due to nonrefractory status epilepticus (NSE), refractory status epilepticus (RSE), and super-refractory status epilepticus (SRSE). METHODS: In 2013 and 2014, all adult patients treated due to status epilepticus (SE) at the university hospitals in Frankfurt, Greifswald, and Marburg were analyzed for healthcare utilization. RESULTS: We evaluated 341 admissions in 316 patients (65.7 ± [standard deviation]18.2 years; 135 male) treated for SE. Mean costs of hospital treatment were €14,946 (median €5,278, range €776-€152,911, €787 per treatment day) per patient per admission, with a mean length of stay (LOS) of 19.0 days (median 14.0, range 1-118). Course of SE had a significant impact on mean costs, with €8,314 in NSE (n = 137, median €4,597, €687 per treatment day, 22.3% of total inpatient costs due to SE), €13,399 in RSE (n = 171, median €7,203, €638/day, 45.0% of total costs, p < 0.001), and €50,488 in SRSE (n = 33, median €46,223, €1,365/day, 32.7% of total costs, p < 0.001). Independent cost-driving factors were SRSE, ventilation, and LOS of >14 days. Overall mortality at discharge was 14.4% and significantly higher in RSE/SRSE (20.1%) than in NSE (5.8%). SIGNIFICANCE: Acute treatment of SE, and particularly SRSE and ventilation, are associated with high hospital costs and prolonged LOS. Extrapolation to the whole of Germany indicates that SE causes hospital costs of >€200 million per year. Along with the demographic change, incidence of SE will increase and costs for hospital treatment and sequelae of SE will rise.

A noninterventional study evaluating the effectiveness and safety of lacosamide added to monotherapy in patients with epilepsy with partial-onset seizures in daily clinical practice: The VITOBA study.

OBJECTIVE: Evidence for the efficacy and safety of adjunctive lacosamide in the treatment of partial-onset seizures (POS) was gained during placebo-controlled clinical trials in patients with treatment-resistant seizures who were taking one to three concomitant antiepileptic drugs (AEDs). The VITOBA study (NCT01098162) evaluated the effectiveness and tolerability of adjunctive lacosamide added to one baseline AED in real-world clinical practice. METHODS: We conducted a 6-month observational study at 112 sites across Germany. Adult patients (≥ 16 years) with POS received lacosamide adjunctive to only one baseline AED. Seizure frequency reduction at the end of the observation period was compared with a 3-month retrospective baseline period. RESULTS: Five hundred seventy-one patients received lacosamide at least once (Safety Set [SS]); 520 provided evaluable seizure records (Full Analysis Set [FAS]); and 499 took in-label dosages of lacosamide (up to 400 mg) and were evaluated for effectiveness (modified FAS). Median baseline seizure frequency was 2.0 per 28 days: 47.1% of patients (235/499, mFAS) took a concomitant sodium channel-blocking (SCB) AED; 38.1% (190/499) had only one lifetime AED; and 18.4% (92/499) were aged ≥ 65 years (mFAS). At the final visit, 72.5% (358/494) of patients showed a ≥ 50% reduction in seizure frequency from baseline, 63.8% (315/494) showed a ≥ 75% reduction, and 45.5% (225/494) were seizure-free. Seizure freedom rates were higher in patients aged ≥ 65 years (56.7%) compared with patients aged <65 years (43.1%), in patients with ≤ 5 years epilepsy duration (52.5%) versus >5 years duration (41.0%), and when added to first monotherapy (60.5%) rather than as a later therapy option. Treatment-emergent adverse events (TEAEs) were reported by 48.5% (277/571) of patients (SS), with a profile similar to that observed in pivotal trials; 466 of patients (81.6%, SS) continued lacosamide therapy after the trial. SIGNIFICANCE: These results suggest that lacosamide use, added to one concomitant AED, was effective at improving seizure control and was well tolerated in patients treated in routine clinical practice.

Predictive value of EFHC1 variants for the long-term seizure outcome in juvenile myoclonic epilepsy.

OBJECTIVE: This study aimed to determine the contribution of EFHC1 variants to the phenotypic variability of juvenile myoclonic epilepsy (JME) and to evaluate their diagnostic value regarding previously identified clinical long-term seizure outcome predictors in a consecutive cohort of patients with JME. METHODS: Thirty-eight probands and three family members affected with JME were studied at a tertiary epilepsy center with a review of their medical records and a subsequent face-to-face interview. All coding EFHC1 exons and adjacent exon/intron boundaries were directly sequenced. RESULTS: The previously reported EFHC1 mutation F229L was found in two cases who presented with early generalized tonic-clonic seizure (GTCS) onset and appeared to be associated with milder subtypes of JME. Variant R294H was identified in two further probands who had a subtype of JME developing from childhood absence epilepsy. However, segregation of the phenotype with this variant could not be confirmed in one family. CONCLUSIONS: Our findings corroborate the heterogeneity of JME as an electroclinical epilepsy syndrome and provide evidence that genetic factors may influence and help predict the long-term seizure outcome in patients with JME.

Clinical predictors of the long-term social outcome and quality of life in juvenile myoclonic epilepsy: 20-65 years of follow-up.

OBJECTIVE: The long-term social outcome in patients with juvenile myoclonic epilepsy (JME) is still controversial. The aim of this study was both to investigate the long-term social outcome in relation to clinical variables and to identify epilepsy-related factors that affect the quality of life (QoL) in JME patients with a follow-up of at least 20 years. METHODS: A retrospective selection of 33 of 90 patients (21 female) from a tertiary epilepsy center diagnosed with JME and followed for ≥20 years (mean 37.8 years) was studied. All patients were evaluated with a thorough review of their medical records, and a subsequent face-to-face or telephone interview. QOLIE-31-P questionnaire (QoL In Epilepsy) and Beck Depression Inventory-II were used to assess the QoL and the presence and severity of depressive symptoms, respectively. RESULTS: Of 33 patients, 18 (54.5%) became seizure-free; in 4 of the patients (22.2%), antiepileptic drug (AED) treatment was discontinued. Early and long-term seizure freedom improves both social adjustment (p = 0.02) and occupational integration (p = 0.02) and associates with a better QoL (odds ratio [OR] 2.25). A high seizure burden highly affects both aspects of personal life-family and work; notably the occurrence of frequent and/or late onset generalized tonic-clonic seizures increases the risk of concomitant diseases (p = 0.05) and lifelong AED treatment (p = 0.03), decreases the patient's employability (p = 0.02), increases the rate of employment disability pension (p = 0.05), and considerably increases public/social spending. Seizure freedom significantly increases the QoL (p = 0.001), whereas more severe courses of epilepsy (OR 3.2), AED side effects (p = 0.04), depression (p = 0.02), and sleep disturbances (OR 2.7) considerably decrease the patient's QoL. SIGNIFICANCE: Although patients with JME are a heterogeneous group, several predictors for the long-term social, family, educational, and occupational outcome have been identified in our study and should be considered in the effort to both improve the patient's QoL as well as preserve economic resources.

Predictors for long-term seizure outcome in juvenile myoclonic epilepsy: 25-63 years of follow-up.

PURPOSE: The long-term seizure outcome of juvenile myoclonic epilepsy (JME) is still controversial; the value of factors that are potentially predictive for seizure outcome remains unclear. The aim of this study was both to investigate the long-term seizure outcome in patients with JME after a follow-up of at least 25 years and to identify factors that are predictive for the seizure outcome. METHODS: Data from 31 patients (19 women) with JME were studied. All of them had a follow-up of at least 25 years (mean 39.1 years) and were reevaluated with a review of their medical records and direct telephone or face-to-face interview. KEY FINDINGS: Of 31 patients 21 (67.7%) became seizure-free; in six of them (28.6%) antiepileptic drug (AED) treatment was discontinued due to seizure freedom. The occurrence of generalized tonic-clonic seizures (GTCS) preceded by bilateral myoclonic seizures (BMS) (p = 0.03), a long duration of epilepsy with unsuccessful treatment (p = 0.022), and AED polytherapy (p = 0.023) were identified as significant predictors for a poor long-term seizure outcome, whereas complete remission of GTCS under AED significantly increased the chance for complete seizure freedom (p = 0.012). The occurrence of photoparoxysmal responses significantly increases the risk of seizure recurrence after AED discontinuation (p = 0.05). SIGNIFICANCE: This study shows conclusively that JME is a heterogeneous epilepsy syndrome. Life-long AED treatment is not necessarily required to maintain seizure freedom. Several long-term outcome predictors that can potentially increase the ability of clinicians and their confidence to recommend different treatment options to patients with JME were identified.

Cerebrospinal fluid promotes survival and astroglial differentiation of adult human neural progenitor cells but inhibits proliferation and neuronal differentiation.

BACKGROUND: Neural stem cells (NSCs) are a promising source for cell replacement therapies for neurological diseases. Growing evidence suggests an important role of cerebrospinal fluid (CSF) not only on neuroectodermal cells during brain development but also on the survival, proliferation and fate specification of NSCs in the adult brain. Existing in vitro studies focused on embryonic cell lines and embryonic CSF. We therefore studied the effects of adult human leptomeningeal CSF on the behaviour of adult human NSCs (ahNSCs). RESULTS: Adult CSF increased the survival rate of adult human NSCs compared to standard serum free culture media during both stem cell maintenance and differentiation. The presence of CSF promoted differentiation of NSCs leading to a faster loss of their self-renewal capacity as it is measured by the proliferation markers Ki67 and BrdU and stronger cell extension outgrowth with longer and more cell extensions per cell. After differentiation in CSF, we found a larger number of GFAP+ astroglial cells compared to differentiation in standard culture media and a lower number of beta-tubulin III+ neuronal cells. CONCLUSIONS: Our data demonstrate that adult human leptomeningeal CSF creates a beneficial environment for the survival and differentiation of adult human NSCs. Adult CSF is in vitro a strong glial differentiation stimulus and leads to a rapid loss of stem cell potential.

First European long-term experience with the orphan drug rufinamide in childhood-onset refractory epilepsy.

OBJECTIVE: Recently, we published the first postmarketing European experience with rufinamide (RUF) in a retrospective 12-week observational study. This follow-up report summarizes the long-term effectiveness and tolerability of RUF after 18 months for the same patient sample. METHODS: In total, 52 of 60 initially included patients from eight centers in Germany and Austria (45 children and 15 adults aged 1-50 years) with various severe and inadequately controlled epilepsy syndromes continued treatment with RUF after the initial 3-month observation period (mean final dose: 38.2+/-17.3mg/kg/day). Efficacy was assessed by seizure frequency evaluated by comparison with baseline frequency. Tolerability was evaluated by analysis of parental report of adverse events and laboratory tests. Responders were defined as patients who achieved a 50% or greater decrease in countable seizures within 18 months of initiating RUF therapy. RESULTS: Mean overall duration of RUF treatment was 14.5 months (range: 3-18 months). Retention rate, defined as the percentage of patients still taking RUF after 18 months, was 41.7% (n=25/60). The overall response rate after 18 months was 26.7% (16/60 patients). The highest response rates were found in the subgroup of patients with Lennox-Gastaut syndrome (LGS, 35.5%) and in patients with other generalized epilepsy syndromes. Complete seizure control was maintained in one patient (1.6%). A total of 73 adverse events were reported in 37 of 60 patients. The most frequently occurring adverse events were fatigue (18.3%), vomiting (15.0%), and loss of appetite (10.0%). Only 4 new adverse events were reported after week 12. No serious adverse events were observed. CONCLUSIONS: The present data suggest that RUF is efficacious and well tolerated in the long-term treatment of children and adults with various epilepsy syndromes and difficult-to-control seizures.

Effectiveness and tolerability of rufinamide in children and adults with refractory epilepsy: first European experience.

OBJECTIVE: The aim of the study was to explore the effectiveness and tolerability of rufinamide in a heterogeneous group of patients with refractory epilepsies in Europe, immediately after the drug became available as an orphan drug for the adjunctive treatment of Lennox-Gastaut syndrome (LGS). METHODS: This observational study was conducted as a collection of retrospective data from multiple centers in Germany and Austria. Clinical course in patients treated with rufinamide was documented. Initial dosage and titration schedule of rufinamide were at the discretion of the treating physician according to medical need. The observation period was 12 weeks. Effectiveness was evaluated by comparing the frequency of seizures with limitations to the countability between baseline and the last 4-week period of observation. RESULTS: The study population consisted of 45 children and 15 adults (mean age: 14.5+/-11.6 years, range: 1-50) with various severe and inadequately controlled epilepsy syndromes, that is, LGS (n=31), idiopathic generalized epilepsy syndromes (n=5), cryptogenic unclassified generalized epilepsy (n=7), and partial epilepsy (n=17). The response rate (50% reduction in countable seizures) was 46.7% (28 of 60 patients) in total; 25.0% experienced a 75% reduction in seizure frequency and 21.7% experienced a 50-75% reduction. Complete seizure control was achieved by 8.3%. The highest response rate was observed in patients with LGS (17/31, 54.8%), and the lowest in patients with partial epilepsy (4/17, 23.5%). Response rate in patients with unclassified generalized epilepsy was 42.8% (3/7 patients). A total of 67 adverse events were reported by 35 of 60 patients. The most frequently occurring adverse events were fatigue (18.3%), vomiting (13.3%), and loss of appetite (10.0%). No serious adverse events were observed. CONCLUSIONS: These preliminary data suggest that rufinamide may be effective and well tolerated in the treatment of children and adults with various epilepsy syndromes and difficult-to-control seizures. The results of our study suggest that the efficacy of rufinamide in patients with generalized epilepsy might be comparable to that in patients with LGS, whereas rufinamide was less effective in patients with partial epilepsy.

Association of ABCB1 genetic variants 3435C>T and 2677G>T to ABCB1 mRNA and protein expression in brain tissue from refractory epilepsy patients.

PURPOSE: There is evidence from studies in rodents that P-glycoprotein (P-gp) overexpression is implicated in the causation of refractory epilepsy. Genetic variants in the human ABCB1 (MDR1) gene were shown to affect the expression levels of the transporter in various tissues and to be associated with refractory epilepsy. However, the effect of the genetic variants on the P-gp level in epileptogenic brain tissue is poorly investigated. In the present study, we examined the impact of putatively functional polymorphisms 3435C>T and 2677G>T in the ABCB1 gene on the ABCB1 mRNA expression and P-gp content in human brain tissue from epileptogenic foci of the patients with refractory epilepsy. METHODS: Fresh brain tissue specimens were obtained from therapy-refractory epilepsy patients during neurosurgery of the epileptogenic focus. We determined the ABCB1 mRNA expression in 23 samples using 5' exonuclease-based real-time polymerase chain reaction (PCR) as well as the P-gp content in 32 samples determined by immunohistochemistry, genotyping was performed by PCR/restriction fragment length polymorphism (RFLP). RESULTS: There was lack of association of 3435C>T and 2677G>T as well as diplotype configurations on ABCB1 mRNA expression and P-gp content in epileptogenic brain tissues. CONCLUSIONS: We cannot exclude an association of ABCB1 variants on P-gp function, but our results suggest that brain ABCB1 mRNA and protein expression is not substantially influenced by major ABCB1 genetic variants thus explaining in part results from case-control studies obtaining lack of association of ABCB1 polymorphisms to the risk of refractory epilepsy.

Juvenile Myoclonic Epilepsy Shows Potential Structural White Matter Abnormalities: A TBSS Study.

Background: Several studies on patients with juvenile myoclonic epilepsy (JME) showed widespread white matter (WM) abnormalities in the brain. The aim of this study was to investigate potential structural abnormalities in JME patients (1) compared to healthy controls, (2) among JME subgroups with or without photoparoxysmal responses (PPR), and (3) in correlation with clinical variables. Methods: A selection of 31 patients with JME (12 PPR positive) and 27 age and gender matched healthy controls (HC) were studied at a tertiary epilepsy center. Fractional anisotropy (FA) was calculated and intergroup differences analyzed using Tract Based Spatial Statistics (TBSS). Results: Compared to HC the JME group showed reduced FA widespread and bilateral in the longitudinal fasciculus, inferior fronto-occipital fasciculus, corticospinal tract, anterior and posterior thalamic radiation, corona radiata, corpus callosum, cingulate gyrus and external capsule (p < 0.01). Subgroup analysis revealed no significant differences of WM alterations between PPR positive and negative patients and with clinical and epilepsy-related factors. Conclusions: Widespread microstructural abnormalities among patients with JME have been identified.Prior findings of frontal and thalamofrontal microstructural abnormalities have been confirmed. Additionally, microstructural abnormalities were found in widespread extra-frontal regions that may help to validate pathophysiological concepts of JME.

Dalfampridine effects on cognition, fatigue, and dexterity.

OBJECTIVES: Dalfampridine exerts beneficial effects on walking ability in a subgroup of patients with multiple sclerosis (MS). These patients are termed "responders". Here, we investigated whether the responder status with respect to mobility measures would determine whether dalfampridine treatment exerts a beneficial effect on other MS symptoms. We therefore assessed walking ability, upper limb function, cognition, fatigue, visual evoked potentials (VEPs), depression, and quality of life in patients before and after dalfampridine treatment. METHODS: Patients with MS and impaired mobility were recruited. Maximal walking distance, timed 25 Foot Walk, nine hole peg test, paced auditory serial addition test (PASAT), fatigue severity scale (FSS), VEPs, Beck Depression Inventory (BDI), EuroQol five dimensional questionnaire, and quality of life visual analogue scale were determined before and after 12-14 days of dalfampridine treatment. Repeated measures analysis of variance was applied to determine the effect of dalfampridine treatment. RESULTS: Of the 34 patients who completed the study, 22 patients were responders and 12 patients nonresponders, according to their performance in mobility measures. Treatment effects for the entire patient cohort were observed for PASAT (p = .029) and BDI (p = .032). Belonging to the responder cohort did not predict the response to treatment in these tests. For the FSS, response to dalfampridine treatment was dependent on the responder status (p = .001) while no effects in the total patient cohort were observed (p = .680). Other neurological functions remained unaltered. For VEP latencies, no significant improvements were detected. CONCLUSION: In this study, we observed beneficial effects of dalfampridine on cognition, depression, and fatigue. These effects were not limited to patients who responded to dalfampridine with improved mobility measures. These findings underscore the need to assess the beneficial effects of dalfampridine on neurological deficits in MS patients in additional randomized clinical trials.

Fear conditioning following unilateral temporal lobectomy: dissociation of conditioned startle potentiation and autonomic learning.

The present study investigated fear-potentiated startle and autonomic learning in brain-lesioned patients in a classical fear-conditioning paradigm. Startle blink and skin conductance responses of 30 patients who underwent unilateral temporal lobectomy because of drug-resistant epilepsy were compared with those of 32 healthy controls. As expected, temporal lobectomy patients showed a general impairment in fear conditioning relative to controls. This impairment did not differ with respect to the affected hemisphere. Moreover, while fear-conditioned startle potentiation in healthy controls was independent of contingency awareness, skin conductance discrimination was only observed for those participants who correctly recognized the stimulus contingencies. Patients who acquired a declarative memory of the contingencies also showed intact skin conductance discrimination but failed to exhibit fear-potentiated startle. The present findings support a two-levels-of-learning account of human fear conditioning and also demonstrate that the amygdala is crucially involved in fear learning.

A splice-site mutation in GABRG2 associated with childhood absence epilepsy and febrile convulsions.

CONTEXT: Missense mutations in the GABRG2 gene, which encodes the gamma 2 subunit of central nervous gamma-aminobutyric acid (GABA)(A) receptors, have recently been described in 2 families with idiopathic epilepsy. In one of these families, the affected individuals predominantly exhibited childhood absence epilepsy and febrile convulsions. OBJECTIVE: To assess the role of GABRG2 in the genetic predisposition to idiopathic absence epilepsies. DESIGN: The GABRG2 gene was screened by single-strand conformation analysis for mutations. Furthermore, a population-based association study assessing a common exon 5 polymorphism (C588T) was carried out. PATIENTS: The sample was composed of 135 patients with idiopathic absence epilepsy and 154 unrelated and ethnically matched controls. RESULTS: A point mutation (IVS6 + 2T-->G) leading to a splice-donor site mutation in intron 6 was found. The mutation, which is predicted to lead to a nonfunctional protein, cosegregates with the disease status in a family with childhood absence epilepsy and febrile convulsions. The association study did not find any significant differences in the allele and genotype frequencies of the common exon 5 polymorphism (C588T) between patients with idiopathic absence epilepsy and controls (P>.35). CONCLUSIONS: Our study identified a splice-donor-site mutation that was probably causing a nonfunctional GABRG2 subunit. This mutation occurred in heterozygosity in the affected members of a single nuclear family, exhibiting a phenotypic spectrum of childhood absence epilepsy and febrile convulsions. The GABRG2 gene seems to confer a rare rather than a frequent major susceptibility effect to common idiopathic absence epilepsy syndromes.

Clinicoradiologic subtypes of Marchiafava-Bignami disease.

The clinical diagnosis of Marchiafava-Bignami disease (MBD) has considerably changed during recent decades with brain MRI providing the opportunity of a reliable in-vivo diagnosis. However, semiologic and neuroimaging characteristics of the currently known spectrum of MBD have not been investigated systematically, and knowledge of clinicoradiologic associations is sketchy. We report an illustrative case with limited callosal involvement on MRI and a favorable outcome and have reviewed literature on clinical and radiologic features in 50 cases of MBD diagnosed in vivo since 1985. Our reviewed data suggest the differentiation of two clinicoradiologic subtypes: Type A is characterized by major impairment of consciousness, T2-hyperintense swelling of the entire corpus callosum on early MRI and poor outcome. Type B shows at most slight impairment of consciousness, partial callosal lesions on MRI and a favorable outcome. Differentiation of these clinicoradiologic subtypes may help resolve inconsistencies of the established clinical classification resulting from new insights into the clinical course and prognosis of MBD by structural neuroimaging.

Valproic acid in normal therapeutic concentration has no neuroprotective or differentiation influencing effects on long term expanded murine neural stem cells.

The antiepileptic drug valproic acid (VPA) has shown neuroprotective effects in different cell types including mesencephalic neural primary cultures. Furthermore, an influence on neural differentiation and neurite outgrowth has been described. Nevertheless, results in this regard are contradictory and data on long term expanded neural stem cells are missing. This is why we investigated possible neuroprotective effects of VPA on fetal mesencephalic neural stem cells (fmNSCs) in vitro, using the neurotoxic agent 1-methyl-4-phenyl-pyridin (MPP+). We also examined potential VPA effects on cell expansion and differentiation and the underlying signaling pathways. In our study, we could exclude any relevant toxic effects of 100 µg/ml and 200 µg/ml VPA on fmNSCs during expansion and differentiation for up to 96 h. MPP+ treatment in concentrations of 30 and 60 µM MPP+ significantly decreased the survival rate of fmNSCs during expansion and differentiation. In all used concentrations, VPA did neither reverse these MPP+ effects when applied simultaneously with MPP+ nor after pre-treatment with VPA for 24 h. In contrast, MPP+ effects were emphasized by VPA pretreatment for 24h when applied during cell expansion. Concerning the self-renewing capacity of fmNSCs, measured by BrdU and Ki67 staining, we did not find any significant influence of VPA. Additionally there was no significant influence of therapeutic VPA dosages on astroglial (GFAP), oligodendroglial (GalC) and neuronal (MAP2) differentiation, measured by immunostaining after 10 days of differentiation. Summing up, we did not find any neuroprotective effects of VPA on fmNSCs in vitro, neither during expansion nor during cell differentiation. Also the self-renewing and differentiation potential of the used fmNSCs was not altered. These findings have implications for the large community of patients having to take VPA on a chronic base, especially in the light of knowledge that a regular cell replacement out of hippocampal adult stem cells is mandatory for the maintenance of normal cognition through adulthood.

Natural course and predictors of spontaneous seizure remission in idiopathic generalized epilepsy: 7-27 years of follow-up.

The spontaneous course of idiopathic generalized epilepsy (IGE) is still controversial. The aim of this study was both to investigate the long-term spontaneous course and to identify factors that are predictive for epilepsy remission in a small cohort of 15 IGE patients (9 women) who refused antiepileptic drug (AED) treatment and therefore never have been treated with AED. All of them were reevaluated with a review of their medical records and direct face-to-face interview; the mean duration of follow-up was 15.3 years. Five (33.3%) of them had absence epilepsy (absence seizures, ABS), 5 had IGE with generalized tonic-clonic seizures (GTCS), and another 5 had both seizure types (IGE with ABS/GTCS). Rate of epilepsy remission was 53.3% with a mean time of seizure freedom of 13.1 years; rate of remission was highest among absence epilepsy patients (80%), followed by IGE with GTCS (60%) and IGE with ABS/GTCS (20%). The frequency of spontaneous generalized interictal epileptiform discharges in electroencephalography is not associated with the long-term seizure outcome (p=0.201) and per se does not require AED treatment. Furthermore, the occurrence of photoparoxysmal responses (p=0.020) as well as the occurrence of more than 3 GTCS during the course (p=0.029) were identified as significant predictors for a poor long-term seizure outcome which makes AED treatment indispensable in these patients. This study underlines the heterogenity of the group of IGE. AED treatment has no impact on the spontaneous course of IGE with ABS and/or GTCS. Several predictors for the long-term seizure outcome in patients with IGE were identified in this study.

Intrameatal thrombosed anterior inferior cerebellar artery aneurysm mimicking a vestibular schwannoma.

Aneurysms of the anterior inferior cerebellar artery (AICA) are a rare entity. Purely intrameatal aneurysms are even rarer. The authors report an intrameatal thrombosed AICA aneurysm mimicking a vestibular schwannoma that was treated by resection and end-to-end anastomosis. This 22-year-old man presented with acute hearing loss, vertigo, and moderate facial palsy. Magnetic resonance imaging showed an atypical intrameatal lesion with dilation of the internal auditory canal. Microsurgical inspection via a retrosigmoid approach and drilling of the posterior wall of the internal auditory canal revealed a thrombosed AICA aneurysm. The aneurysm was excised, and an end-to-end suture was performed to restore AICA continuity. Intraoperative indocyanine green videoangiography as well as postoperative digital substraction angiography showed a good revascularization. Intrameatal AICA aneurysms may present with symptoms similar to vestibular schwannomas. End-to-end reanastomosis after aneurysm resection is a treatment option when clipping is impossible.