Neurology January 2009 Volume 72 Issue 3

Background: Although surgical resection has been an important alternative treatment for patients with intractable epilepsy related to focal cortical dysplasia (FCD), the prognostic relevance of the degree of pathologic severity is controversial and there has been only limited information regarding the prognostic factors involved in the surgical treatment of refractory epilepsy in patients with FCD.Methods: We undertook the present study to assess whether the pathologic subtypes of FCD affect surgical outcomes in patients with drug-resistant epilepsy. We also studied the prognostic roles of clinical factors and various diagnostic modalities in the surgical treatment.Results: A total of 166 consecutive patients were included. By univariate analysis, incomplete resection of epileptogenic area (p < 0.001), mild pathologic features (p = 0.01), and the presence of secondary tonic clonic seizures (2GTCS) (p = 0.05) were associated with poor surgical outcomes. There was a strong tendency for patients with severe pathologic features to have MRI abnormalities (p < 0.001). Incomplete resection of epileptogenic area (p < 0.001) and mild pathologic features (p = 0.02) were poor independent outcome predictors on multivariate analysis. The results of MRI, scalp EEG, fluorodeoxyglucose-PET, and ictal SPECT were not associated with surgical outcomes.Conclusions: Our study shows that there is a strong tendency for patients with severe pathologic features to have MRI abnormalities, and patients with incomplete resection, mild pathologic features, or the presence of secondary tonic clonic seizures have a high chance of a poorer surgical outcome.(C)2009AAN Enterprises, Inc.

Background: Long QT syndrome (LQTS) typically presents with syncope, seizures, or sudden death. Patients with LQTS have been misdiagnosed with a seizure disorder or epilepsy and treated with antiepileptic drug (AED) medication. The gene, KCNH2, responsible for type 2 LQTS (LQT2), was cloned originally from the hippocampus and encodes a potassium channel active in hippocampal astrocytes. We sought to test the hypothesis that a "seizure phenotype" was ascribed more commonly to patients with LQT2.Methods: Charts were reviewed for 343 consecutive, unrelated patients (232 females, average age at diagnosis 27 +/- 18 years, QTc 471 +/- 57 msec) clinically evaluated and genetically tested for LQTS from 1998 to 2006 at two large LQTS referral centers. A positive seizure phenotype was defined as the presence of either a personal or family history of seizures or history of AED therapy.Results: A seizure phenotype was recorded in 98/343 (29%) probands. A seizure phenotype was more common in LQT2 (36/77, 47%) than LQT1 (16/72, 22%, p < 0.002) and LQT3 (7/28, 25%, p < 0.05, NS). LQT1 and LQT3 combined cohorts did not differ significantly from expected, background rates of a seizure phenotype. A personal history of seizures was more common in LQT2 (30/77, 39%) than all other subtypes of LQTS (11/106, 10%, p < 0.001).Conclusions: A diagnostic consideration of epilepsy and treatment with antiepileptic drug medications was more common in patients with LQT2. Like noncardiac organ phenotypes observed in other LQTS-susceptibility genes such as KCNQ1/deafness and SCN5A/gastrointestinal symptoms, this novel LQT2-epilepsy association raises the possibility that LQT2-causing perturbations in the KCNH2-encoded potassium channel may confer susceptibility for recurrent seizure activity.(C)2009AAN Enterprises, Inc.

Background: The combination of early-onset, progressive parkinsonism with pyramidal tract signs has been known as pallido-pyramidal or parkinsonian-pyramidal syndrome since the first description by Davison in 1954. Very recently, a locus was mapped in a single family with an overlapping phenotype, and an FBXO7 gene mutation was nominated as the likely disease cause.Methods: We performed clinical and genetic studies in two families with early-onset, progressive parkinsonism and pyramidal tract signs.Results: An FBXO7 homozygous truncating mutation (Arg498Stop) was found in an Italian family, while compound heterozygous mutations (a splice-site IVS7 + 1G/T mutation and a missense Thr22Met mutation) were present in a Dutch family. We also found evidence of expression of novel normal splice-variants of FBXO7. The phenotype associated with FBXO7 mutations consisted of early-onset, progressive parkinsonism and pyramidal tract signs, thereby matching clinically the pallido-pyramidal syndrome of Davison. The parkinsonism exhibits varying degrees of levodopa responsiveness in different patients.Conclusions: We conclusively show that recessive FBXO7 mutations cause progressive neurodegeneration with extrapyramidal and pyramidal system involvement, delineating a novel genetically defined entity that we propose to designate as PARK15. Understanding how FBXO7 mutations cause disease will shed further light on the molecular mechanisms of neurodegeneration, with potential implications also for more common forms of parkinsonism, such as Parkinson disease and multiple system atrophy.(C)2009AAN Enterprises, Inc.

Objective: High neuroticism has been associated with a greater risk of dementia, and an active/socially integrated lifestyle with a lower risk of dementia. The aim of the current study was to explore the separate and combined effects of neuroticism and extraversion on the risk of dementia, and to examine whether lifestyle factors may modify this association.Methods: A population-based cohort of 506 older people with no dementia from the Kungsholmen Project, Stockholm, Sweden, was followed up for an average of 6 years. Personality traits were assessed using the Eysenck Personality Inventory. Dementia was diagnosed by specialists according to DSM-III-R criteria.Results: Neither high neuroticism nor low extraversion alone was related to significantly higher incidence of dementia. However, among people with an inactive or socially isolated lifestyle, low neuroticism was associated with a decreased dementia risk (hazard ratio [HR] = 0.51, 95% confidence interval [CI] = 0.27-0.96). When compared to persons with high neuroticism and high extraversion, a decreased risk of dementia was detected in individuals with low neuroticism and high extraversion (HR = 0.51, 95% CI = 0.28-0.94), but not among persons with low neuroticism and low extraversion (HR = 0.95, 95% CI = 0.57-1.60), nor high neuroticism and low extraversion (HR = 0.97 95% CI = 0.57-1.65). Stratified analysis by lifestyle showed that the inverse association of low neuroticism and high extraversion in combination was present only among the inactive or socially isolated persons.Conclusion: Low neuroticism in combination with high extraversion is the personality trait associated with the lowest dementia risk; however, among socially isolated individuals even low neuroticism alone seems to decrease dementia risk.(C)2009AAN Enterprises, Inc.

Background: Amyloid-beta protein (A[beta]) plays a key role in Alzheimer disease (AD) and is also implicated in cerebral small vessel disease. Serum total homocysteine (tHcy) is a risk factor for small vessel disease and cognitive impairment and correlates with plasma A[beta] levels. To determine whether this association results from a common pathophysiologic mechanism, we investigated whether vitamin supplementation-induced reduction of tHcy influences plasma A[beta] levels in the Vitamin Intervention in Stroke Prevention (VISP) study.Methods: Two groups of 150 patients treated with either the high-dose or low-dose formulation of pyridoxine, cobalamin, and folic acid in a randomized, double-blind fashion were selected among the participants in the VISP study without recurrent stroke during follow-up and in the highest 10% of the distribution for baseline tHcy levels. Concentrations of plasma A[beta] with 40 (A[beta]40) and 42 (A[beta]42) amino acids were measured at baseline and at the 2-year visit.Results: tHcy levels significantly decreased with vitamin supplementation in both groups. tHcy were strongly correlated with A[beta]40 but not A[beta]42 concentrations. There was no difference in the change in A[beta]40, A[beta]42 (p = 0.40, p = 0.35), or the A[beta]42/A[beta]40 ratio over time (p = 0.86) between treatment groups. A[beta] measures were not associated with cognitive change.Conclusions: This double-blind randomized controlled trial of vitamin therapy demonstrates a strong correlation between serum tHcy and plasma A[beta]40 concentrations in subjects with ischemic stroke. Treatment with high dose vitamins does not, however, influence plasma levels of A[beta], despite their effect on lowering tHcy. Our results suggest that although tHcy is associated with plasma A[beta]40, they may be regulated by independent mechanisms.(C)2009AAN Enterprises, Inc.