Reduced dendritic arborization and hyperexcitability of pyramidal neurons in a Scn1b-based model of Dravet syndrome

Epileptic encephalopathies, including Dravet syndrome, are severe treatment-resistant epilepsies with developmental regression. We examined a mouse model based on a human β1 sodium channel subunit (Scn1a) mutation. Homozygous mutant mice shared phenotypic features and pharmaco-sensitivity with Dravet syndrome. Patch-clamp analysis showed that mutant subicular and layer 2/3 pyramidal neurons had increased action potential firing rates, presumably as a consequence of their increased input resistance. These changes were not seen in L5 or CA1 pyramidal neurons. This raised the concept of a regional seizure mechanism that was supported by data showing increased spontaneous synaptic activity in the subiculum but not CA1. Importantly, no changes in firing or synaptic properties of gamma-aminobutyric acidergic interneurons from mutant mice were observed, which is in contrast withScn1a-based models of Dravet syndrome. Morphological analysis of subicular pyramidal neurons revealed reduced dendritic arborization. The antiepileptic drug retigabine, a K⁺ channel opener that reduces input resistance, dampened action potential firing and protected mutant mice from thermal seizures. These results suggest a novel mechanism of disease genesis in genetic epilepsy and demonstrate an effective mechanism-based treatment of the disease.

Brain 2014

Swiss Cheese Striatum Clinical Implications

Objective  To determine the clinical features associated with SCS detected on MRI scans.

Design, Setting, and Participants  A blinded, retrospective case-control study using medical records from 2000 to 2007 obtained from an MRI database at the Mayo Clinic in Rochester, Minnesota, of residents 40 years of age or older of Olmsted County, Minnesota, who had extensive Mayo Clinic medical records and MRI reports suggestive of SCS. Cases with a severe form of SCS (n = 27) were randomly selected for comparison with age-, sex-, and examination year–matched controls (n = 52) with a minimal form of SCS or no SCS.

Exposure  Magnetic resonance imaging.

Main Outcomes and Measures  Associations of clinical and imaging features with the presence of a severe form of SCS. Medical records were reviewed for clinical features such as parkinsonism, dementia, and vascular risk factors. The MRI scans were visually scored for degree of leukoaraiosis, central atrophy, and cortical atrophy.

Results  No significant differences were found between those with a severe form of SCS and controls in rates of parkinsonism (19% vs 17%; odds ratio, 1.09 [95% CI, 0.28-4.16]) or dementia of any type (30% vs 21%; odds ratio, 1.57 [95% CI, 0.48-5.13]). Vascular risk factors were not significantly different between groups. Swiss cheese striatum correlated with degree of leukoaraiosis (P < .001). Potential associations with visualized cortical atrophy (P = .01), nonobstructive urinary incontinence (18.5% vs 3.9%; P = .04), and syncope (37% vs 9.6%; P = .01) did not hold up after correction for the false discovery rate.

Conclusions and Relevance  Our study suggests that marked cribriform change in the striatum was not associated with the development of extrapyramidal clinical disorders, including parkinsonism. The association of SCS with leukoaraiosis suggests that it is part of a more generalized cerebrovascular process. Skepticism is called for when attributing clinical symptoms to this MRI finding.

JAMA Neurology 2014

Multiple System Atrophy and Amyotrophic Lateral Sclerosis in a Family With Hexanucleotide Repeat Expansions in C9orf72

Importance  Here we report a family with coexistence of multiple system atrophy (MSA) and amyotrophic lateral sclerosis (ALS) with hexanucleotide repeat expansions in C9orf72.

Observations  A 65-year-old woman had a 2-year history of ataxia with autonomic dysfunction but without motor neuron signs. She was diagnosed as having MSA based on her clinical history and the hot cross bun sign on brain magnetic resonance imaging. Her 62-year-old brother had progressive weakness, fasciculations, hyperreflexia, and active denervation on electromyography without cerebellar ataxia. He was diagnosed as having ALS. Both patients had a greater than 1000/2 hexanucleotide expansion in C9orf72.

Conclusions and Relevance  Patients with hexanucleotide repeat expansions in C9orf72 can present with MSA as well as ALS or frontotemporal dementia. We report this family with coexisting MSA and ALS, highlighting the phenotypic variability in neurologic presentations with hexanucleotide repeat expansions in C9orf72

JAMA Neurology 2014

Diagnostic precision of PET imaging and functional MRI in disorders of consciousness: a clinical validation study

Methods

For this clinical validation study, we included patients referred to the University Hospital of Liège, Belgium, between January, 2008, and June, 2012, who were diagnosed by our unit with unresponsive wakefulness syndrome, locked-in syndrome, or minimally conscious state with traumatic or non-traumatic causes. We did repeated standardised clinical assessments with the Coma Recovery Scale—Revised (CRS—R), cerebral 18F-fluorodeoxyglucose (FDG) PET, and fMRI during mental activation tasks. We calculated the diagnostic accuracy of both imaging methods with CRS—R diagnosis as reference. We assessed outcome after 12 months with the Glasgow Outcome Scale—Extended.

Findings

We included 41 patients with unresponsive wakefulness syndrome, four with locked-in syndrome, and 81 in a minimally conscious state (48=traumatic, 78=non-traumatic; 110=chronic, 16=subacute). 18F-FDG PET had high sensitivity for identification of patients in a minimally conscious state (93%, 95% CI 85—98) and high congruence (85%, 77—90) with behavioural CRS—R scores. The active fMRI method was less sensitive at diagnosis of a minimally conscious state (45%, 30—61) and had lower overall congruence with behavioural scores (63%, 51—73) than PET imaging. 18F-FDG PET correctly predicted outcome in 75 of 102 patients (74%, 64—81), and fMRI in 36 of 65 patients (56%, 43—67). 13 of 42 (32%) of the behaviourally unresponsive patients (ie, diagnosed as unresponsive with CRS—R) showed brain activity compatible with (minimal) consciousness (ie, activity associated with consciousness, but diminished compared with fully conscious individuals) on at least one neuroimaging test; 69% of these (9 of 13) patients subsequently recovered consciousness.

Interpretation

Cerebral 18F-FDG PET could be used to complement bedside examinations and predict long-term recovery of patients with unresponsive wakefulness syndrome. Active fMRI might also be useful for differential diagnosis, but seems to be less accurate.

Funding

The Belgian National Funds for Scientific Research (FNRS), Fonds Léon Fredericq, the European Commission, the James McDonnell Foundation, the Mind Science Foundation, the French Speaking Community Concerted Research Action, the University of Copenhagen, and the University of Liège.

Lancet 2014

Structural MRI correlates of apathy symptoms in older persons without dementia AGES-Reykjavik Study

Objective: We aimed to investigate the relation between apathy symptoms and structural brain changes on MRI, including white matter lesions (WMLs) and atrophy, in a large cohort of older persons.

Methods: Cross-sectional analyses are based on 4,354 persons without dementia (aged 76 ± 5 years) participating in the population-based Age, Gene/Environment Susceptibility–Reykjavik Study. Apathy symptoms were assessed with 3 items from the 15-item Geriatric Depression Scale. Brain volumes and total WML volume were estimated on 1.5-tesla MRI using an automated segmentation program; regional WML load was calculated using a semiquantitative scale. Regression analyses were adjusted for age, sex, education, intracranial volume, vascular risk factors, physical activity, brain infarcts, depressive symptoms, antidepressants, and cognitive status.

Results: Compared to those with <2 apathy symptoms, participants with ≥2 apathy symptoms (49% of the cohort) had significantly smaller gray matter volumes (mean adjusted difference −3.6 mL, 95% confidence interval [CI] −6.2 to −1.0), particularly in the frontal and temporal lobes; smaller white matter volumes (mean adjusted difference −1.9 mL, 95% CI −3.6 to −0.3), mainly in the parietal lobe; and smaller thalamus volumes. They were also more likely to have WMLs in the frontal lobe (adjusted odds ratio = 1.08, 95% CI 0.9–1.3). Excluding participants with a depression diagnosis did not change the associations

Neurology 2014

Electrical source imaging in cortical malformation–related epilepsy: A prospective EEG-SEEG concordance study

Objective

Delineation of the epileptogenic zone (EZ) in refractory epilepsy related to malformations of cortical development (MCDs) often requires intracranial electroencephalography (EEG) recordings, especially in cases of negative magnetic resonance imaging (MRI) or discordant MRI and video-EEG findings. It is therefore crucial to promote the development of noninvasive methods such as electrical source imaging (ESI). We aimed to (1) analyze the localization concordance of ESI derived from interictal discharges and EZ estimated by stereo-EEG (SEEG); (2) compare the concordance of ESI, MRI, and electroclinical correlations (ECCs) with SEEG-EZ; and (3) assess ESI added value in the EZ localization.

Methods

We prospectively analyzed 28 consecutive patients undergoing presurgical investigation for MCD-related refractory epilepsy in 2009–2012. ESI derived from 64-channel scalp EEG was interpreted with blinding to, and subsequently compared with, SEEG-estimated EZ. Anatomic concordance of ESI with SEEG-EZ was compared with that of video-EEG and MRI. We further assessed ESI added value to ECC and MRI.

Results

Twelve patients (43%) had temporal and 16 (57%) had extratemporal epilepsy. MRI was negative in 11 (39%) and revealed a cortical malformation in 17 (61%). ESI was fully concordant with the EZ in 10 (36%) and partly concordant in 15 (53%). ECC presented a full and partial concordance with EZ in 11% and 82% of cases, respectively, and MRI in 11% and 46%, respectively. Of 11 patients with negative MRI, ESI was fully concordant with the EZ in 7 (64%) and partly concordant in 4 (36%). ESI correctly confirmed restricted or added localizations to ECC and MRI in 12 (43%) of 28 patients and in 8 (73%) of 11 patients with negative MRI.

Significance

ESI contributes to estimating the EZ in MCD-related epilepsy. The added value of ESI to ECC is particularly high in patients with MCD and negative MRI, who represent the most challenging cases for epilepsy surgery.

Epilepsia 2014

Italian recommendations for Lambert–Eaton myasthenic syndrome (LEMS) management

Lambert–Eaton myasthenic syndrome (LEMS) is a pre-synaptic disorder of the neuromuscular and autonomic transmission mediated by antibodies to voltage-gated calcium channels at the motor nerve terminal. LEMS is a quite rare and probably under-diagnosed disease: the onset may be slow and clinical signs are typically fluctuating, thus adding to the delay in diagnosis. LEMS weakness typically involves lower and upper limbs and the proximal muscles are predominantly affected. A significant proportion of patients also have dysfunction of the autonomic nervous system that may include dry mouth, constipation, blurred vision, impaired sweating, and orthostatic hypotension. LEMS recognition is based on clinical, electrophysiological and immunological criteria. Nearly 50–60 % of patients with LEMS have an underlying tumour that, in almost all cases, is a small-cell lung cancer; the onset of neurological symptoms generally precedes tumour detection. A careful screening for the early detection of the possible associated cancer is a crucial step for optimal disease management. The Italian Working Group on Myasthenic Syndromes developed diagnostic and therapeutic algorithms that could serve in routine clinical practice as tools for a patient-tailored approach.

Neurological Sciences 2014