The role of clinical and neuroimaging features in the diagnosis of CADASIL.

BACKGROUND: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most common familial cerebral small vessel disease, caused by NOTCH3 gene mutations. The aim of our study was to identify clinical and neuroradiological features which would be useful in identifying which patients presenting with lacunar stroke and TIA are likely to have CADASIL. METHODS: Patients with lacunar stroke or TIA were included in the present study. For each patient, demographic and clinical data were collected. MRI images were centrally analysed for the presence of lacunar infarcts, microbleeds, temporal lobe involvement, global atrophy and white matter hyperintensities. RESULTS: 128 patients (mean age 56.3 ± 12.4 years) were included. A NOTCH3 mutation was found in 12.5% of them. A family history of stroke, the presence of dementia and external capsule lesions on MRI were the only features significantly associated with the diagnosis of CADASIL. Although thalamic, temporal pole gliosis and severe white matter hyperintensities were less specific for CADASIL diagnosis, the combination of a number of these factors together with familial history for stroke result in a higher positive predictive value and specificity. CONCLUSIONS: A careful familial history collection and neuroradiological assessment can identify patients in whom NOTCH3 genetic testing has a higher yield.

Physical Therapy Versus a General Exercise Programme in Patients with Hoehn Yahr Stage II Parkinson's Disease: A Randomized Controlled Trial.

BACKGROUND AND OBJECTIVE: Several studies suggest that general exercise (GE) and physical therapy programmes (PT) improve the outcomes of Parkinson's disease (PD) patients; however, the available data do not allow a determination of which treatment is more effective. Our study aims to compare the effects of physiotherapy and general exercise in Parkinson's disease. METHODS: Design and setting: Randomized controlled trial -general hospital outpatient clinic. The participants were patients with Hoehn Yahr stage II PD. Two randomized groups: one receiving PT and one receiving GE. The outcome measures were the FIM, Hamilton Rating Scale, TUG test, and UPDRS. RESULTS: FIM median scores improved by 3 points in the PT group after treatment, and the improvements were maintained at follow-up. The GE FIM median scores were unchanged after treatment and were reduced by 1 point at follow-up (p < 0.05). The TUG test time was reduced in the PT group but increased in the GE group with a 3-second difference between groups at follow-up, suggesting improved functional mobility after specific physiotherapy (p < 0.05). The UPDRS median score change from baseline was significantly different between the two groups at the end of treatment (6.5 points) and at follow-up (11 points), with a benefit for the physiotherapy group. CONCLUSIONS: Physiotherapy seems to be more effective than a generic exercise programme in patients with Hoehn Yahr stage II PD.

Clinical Pregenetic Screening for Stroke Monogenic Diseases: Results From Lombardia GENS Registry.

BACKGROUND AND PURPOSE: Lombardia GENS is a multicentre prospective study aimed at diagnosing 5 single-gene disorders associated with stroke (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, Fabry disease, MELAS [mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes], hereditary cerebral amyloid angiopathy, and Marfan syndrome) by applying diagnostic algorithms specific for each clinically suspected disease METHODS: We enrolled a consecutive series of patients with ischemic or hemorrhagic stroke or transient ischemic attack admitted in stroke units in the Lombardia region participating in the project. Patients were defined as probable when presenting with stroke or transient ischemic attack of unknown etiopathogenic causes, or in the presence of <3 conventional vascular risk factors or young age at onset, or positive familial history or of specific clinical features. Patients fulfilling diagnostic algorithms specific for each monogenic disease (suspected) were referred for genetic analysis. RESULTS: In 209 patients (57.4±14.7 years), the application of the disease-specific algorithm identified 227 patients with possible monogenic disease. Genetic testing identified pathogenic mutations in 7% of these cases. Familial history of stroke was the only significant specific feature that distinguished mutated patients from nonmutated ones. The presence of cerebrovascular risk factors did not exclude a genetic disease. CONCLUSIONS: In patients prescreened using a clinical algorithm for monogenic disorders, we identified monogenic causes of events in 7% of patients in comparison to the 1% to 5% prevalence reported in previous series.

Novel GNAL mutation with intra-familial clinical heterogeneity: Expanding the phenotype.

INTRODUCTION: Mutations in GNAL have been associated with adult-onset cranio-cervical dystonia, but a limited number of cases have been reported so far and the clinical spectrum associated with this gene still needs to be fully characterized. METHODS: We identified an Italian family with adult-onset, dominantly-inherited dystonia whose members presented with different combinations of dystonia affecting the cervical, oro-mandibular and laryngeal regions associated with prominent tremor in some cases. Pure asymmetric upper limb dystonic tremor was present in one of the members and jerky cervical dystonia was also observed. A dedicate dystonia gene panel (Illumina) was used to screen for dystonia-associated genes and Sanger sequencing was performed to confirm results obtained and to perform segregation analysis. RESULTS: A novel single-base mutation in GNAL exon 9 (c.628G>A; p.Asp210Asn) leading to an aminoacidic substitution was identified and confirmed by Sanger sequencing. In silico prediction programmes as well as segregation analysis confirmed its pathogenicity. Clinically, no generalization of dystonia was observed after onset and DBS lead to an excellent motor outcome in two cases. CONCLUSION: We report a novel GNAL mutation and expand the clinical spectrum associated with mutations in this gene to comprise pure asymmetric dystonic tremor and a jerky cervical phenotype partially mimicking DYT11 positive cases.

Extrapyramidal and cognitive signs in amyotrophic lateral sclerosis: A population based cross-sectional study.

Our objective was to assess the association between amyotrophic lateral sclerosis (ALS) and other neurodegenerative diseases such as Alzheimer's disease (AD), frontotemporal dementia (FTD) and Parkinson's disease (PD). From May 2007 through August 2012 we investigated 146 patients with newly diagnosed ALS and 146 age- and gender-matched controls. Each individual was screened for cardinal extrapyramidal signs (neurological examination) and cognitive dysfunction (Mini Mental State Examination, MMSE and Frontal Assessment Battery, FAB). Results demonstrated that rigidity was present in 8.2% of cases and 2.1% of controls (adjusted odds ratio, adjOR 5.7; 95% CI 1.5-22.0). The corresponding percentages for bradykinesia and postural instability were, respectively, 8.2 vs. 2.7% (adjOR 4.8; 95% CI 1.4-16.5) and 2.7 vs. 9.6% (adjOR 0.3; 95% CI 0.1-0.9). FAB ≤ 13.4 was recorded in 24.8 vs. 9.6%; adjOR 2.9; 95% CI 1.5-5.7). Tremor and abnormal FAB score were predicted by an older age at onset while an abnormal FAB score was associated with cramps and family history of neurodegenerative diseases. In conclusion, our data support the notion that newly diagnosed ALS carries a higher than expected risk of extrapyramidal signs and FTD.

Comprehensive educational plan for patients with epilepsy and comorbidity (EDU-COM): a pragmatic randomised trial.

BACKGROUND: The impact of educational strategies in the management of adverse treatment effects and drug interactions in adult patients with epilepsy with comorbidities remains undetermined. OBJECTIVE: The EDU-COM study is a randomised, pragmatic trial investigating the effect of a patient-tailored educational plan in patients with epilepsy with comorbidity. METHODS: 174 adult patients with epilepsy with chronic comorbidities, multiple-drug therapy and reporting at least one adverse treatment effect and/or drug interaction at study entry were randomly assigned to the educational plan or usual care. The primary endpoint was the number of patients becoming free from adverse treatment events and/or drug interactions after a 6-month follow-up. The number of adverse treatment events and drug interactions, health-related quality of life (HRQOL) summary score changes and the monetary costs of medical contacts and drugs were assessed as secondary outcomes. RESULTS: The primary endpoint was met by 44.0% of patients receiving the educational plan versus 28.9% of those on usual care (p=0.0399). The control group reported a significantly higher risk not to meet successfully the primary endpoint at the end of the study: OR (95% CI) of 2.29 (1.03 to 5.09). A separate analysis on drug adverse effects and drug interactions showed that the latter were more sensitive to the effect of educational treatment. Quality of life and costs were not significantly different in the two groups. CONCLUSIONS: A patient-tailored educational strategy is effective in reducing drug-related problems (particularly drug interactions) in epilepsy patients with chronic comorbidities, without adding significant monetary costs. Registered at ClinicalTrials.gov, identifier NCT01804322, (http://www.clinicaltrials.gov).

ApoE epsilon4 allele and disease duration affect verbal learning in mild temporal lobe epilepsy.

PURPOSE: To clarify the possible role of other factors including the ApoE epsilon4 allele for memory decline in temporal lobe epilepsy (TLE). METHODS: We conducted a neuropsychological and molecular study in 138 consecutive patients (78 female patients; mean age, 50.2 years, SD +/- 17.9; range, 14 to 87 years) with mild nonlesional TLE, who rarely or never had seizures at long-term follow-up. The mean age at seizure onset was 33.0 years (SD, +/-21.7), and the mean duration of epilepsy was 17.1 years (SD, +/-15.7). RESULTS: Thirty-four (25%) of 138 patients had test scores indicating verbal learning deficit (VLD). The presence of an ApoE epsilon4 allele was associated with an increased risk of VLD (OR, 4.18; 95% CI, 1.66-10.55). The effect of the ApoE genotype was independent of both the age at epilepsy onset and disease duration as well as of a low educational level, which were separately associated with VLD (p values = 0.045, 0.001, and 0.001, respectively). A significant linear trend (p = 0.005) was seen in the relation between disease duration and cognitive impairment, with the highest risk being in patients with an epilepsy duration > or =25.5 years (OR, 7.06; 95% CI, 1.67-29.85), especially if they carried the epsilon4 allele (OR, 32.29; 95% CI, 5.23-195.72). CONCLUSIONS: These results provide evidence for an alteration in cognitive performance as a function of the presence of the ApoE epsilon4 allele and point to the critical role of disease duration itself for cognitive impairment in TLE.