Alexandre Croquelois

Mutations in Eml1 lead to ectopic progenitors and neuronal heterotopia in mouse and human

Neuronal migration disorders such as lissencephaly and subcortical band heterotopia are associated with epilepsy and intellectual disability. DCX, PAFAH1B1 and TUBA1A are mutated in these disorders; however, corresponding mouse mutants do not show heterotopic neurons in the neocortex. In contrast, spontaneously arisen HeCo mice display this phenotype, and our study revealed that misplaced apical progenitors contribute to heterotopia formation. While HeCo neurons migrated at the same speed as wild type, abnormally distributed dividing progenitors were found throughout the cortical wall from embryonic day 13. We identified Eml1, encoding a microtubule-associated protein, as the gene mutated in HeCo mice. Full-length transcripts were lacking as a result of a retrotransposon insertion in an intron. Eml1 knockdown mimicked the HeCo progenitor phenotype and reexpression rescued it. We further found EML1 to be mutated in ribbon-like heterotopia in humans. Our data link abnormal spindle orientations, ectopic progenitors and severe heterotopia in mouse and human.

Stroke aphasia: 1,500 consecutive cases.

Background: To study the characteristics of vascular aphasia in a cohort of patients with a first-ever stroke. Methods: All patients admitted to the Lausanne neurology department for a first-ever stroke between 1979 and 2004 were included. Neurological examination including language was performed on admission. Stroke risk factors, stroke origin and location, associated symptoms and Rankin scale scores were recorded for each patient. The influence of these factors on aphasia frequency and subtypes was analyzed using logistic regression models. Results: 1,541 (26%) of patients included in this study had aphasia. The more frequent clinical presentations were expressive-receptive aphasia (38%) and mainly expressive aphasia (37%), whereas mainly receptive aphasia was less frequently observed (25%). In ischemic stroke, the frequency of aphasia increased with age (55% of nonaphasic vs. 61% of aphasic patients were more than 65 years old), female sex (40% of women in the nonaphasia group vs. 44% in the aphasia group) and risk factors for cardioembolic origin (coronary heart disease 20 vs. 26% and atrial fibrillation 15 vs. 24%). Stroke aphasia was more likely associated with superficial middle cerebral artery (MCA) stroke and leads to relevant disability. Clinical subtypes depended on stroke location and associated symptoms. Exceptions to the classic clinical-topographic correlations were not rare (26%). Finally, significant differences were found for patients with crossed aphasia in terms of stroke origin and aphasia subtypes. Conclusions: Risk factors for stroke aphasia are age, cardioembolic origin and superficial MCA stroke. Exceptions to classic clinical-topographic correlations are not rare. Stroke aphasia is associated with relevant disability. Stroke location and associated symptoms strongly influence aphasia subtypes.

Characterization of the HeCo Mutant Mouse: A New Model of Subcortical Band Heterotopia Associated with Seizures and Behavioral Deficits

In human, neuronal migration disorders are commonly associated with developmental delay, mental retardation, and epilepsy. We describe here a new mouse mutant that develops a heterotopic cortex (HeCo) lying in the dorsolateral hemispheric region, between the homotopic cortex (HoCo) and subcortical white matter. Cross-breeding demonstrated an autosomal recessive transmission. Birthdating studies and immunochemistry for layer-specific markers revealed that HeCo formation was due to a transit problem in the intermediate zone affecting both radially and tangentially migrating neurons. The scaffold of radial glial fibers, as well as the expression of doublecortin is not altered in the mutant. Neurons within the HeCo are generated at a late embryonic age (E18) and the superficial layers of the HoCo have a correspondingly lower cell density and layer thickness. Parvalbumin immunohistochemistry showed the presence of gamma-aminobutyric acidergic cells in the HeCo and the mutant mice have a lowered threshold for the induction of epileptic seizures. The mutant showed a developmental delay but, in contrast, memory function was relatively spared. Therefore, this unique mouse model resembles subcortical band heterotopia observed in human. This model represents a new and rare tool to better understand cortical development and to investigate future therapeutic strategies for refractory epilepsy.

Hippocampal volume predicts fluid intelligence in musically trained people

Recently, age‐related hippocampal (HP) volume loss could be associated with a decrease in general fluid intelligence (gF). In the present study we investigated whether and how extensive musical training modulates human HP volume and gF performance. Previously, some studies demonstrated positive effects of musical training on higher cognitive functions such as learning and memory, associated with neural adaptations beyond the auditory domain. In order to detect possible associations between musical training and gF, we bilaterally segmented the HP formation and assessed the individual gF performance of people with different levels of musical expertise. Multiple regression analyses revealed that HP volume predicts gF in musicians but not in nonmusicians; in particular, bilaterally enhanced HP volume is associated with increased gF exclusively in musically trained people (amateurs and experts). This result suggests that musical training facilitates the recruitment of cognitive resources, which are essential for gF and linked to HP functioning. Musical training, even at a moderate level of intensity, can thus be considered as a potential strategy to decelerate age‐related effects of cognitive decline.

Diagnostic yield of short-term video-EEG monitoring for epilepsy and PNESs: a European assessment.

INTRODUCTION Although long-term video-EEG monitoring (LVEM) is routinely used to investigate paroxysmal events, short-term video-EEG monitoring (SVEM) lasting <24 h is increasingly recognized as a cost-effective tool. Since, however, relatively few studies addressed the yield of SVEM among different diagnostic groups, we undertook the present study to investigate this aspect. METHODS We retrospectively analyzed 226 consecutive SVEM recordings over 6 years. All patients were referred because routine EEGs were inconclusive. Patients were classified into 3 suspected diagnostic groups: (1) group with epileptic seizures, (2) group with psychogenic nonepileptic seizures (PNESs), and (3) group with other or undetermined diagnoses. We assessed recording lengths, interictal epileptiform discharges, epileptic seizures, PNESs, and the definitive diagnoses obtained after SVEM. RESULTS The mean age was 34 (±18.7) years, and the median recording length was 18.6 h. Among the 226 patients, 127 referred for suspected epilepsy - 73 had a diagnosis of epilepsy, none had a diagnosis of PNESs, and 54 had other or undetermined diagnoses post-SVEM. Of the 24 patients with pre-SVEM suspected PNESs, 1 had epilepsy, 12 had PNESs, and 11 had other or undetermined diagnoses. Of the 75 patients with other diagnoses pre-SVEM, 17 had epilepsy, 11 had PNESs, and 47 had other or undetermined diagnoses. After SVEM, 15 patients had definite diagnoses other than epilepsy or PNESs, while in 96 patients, diagnosis remained unclear. Overall, a definitive diagnosis could be reached in 129/226 (57%) patients. CONCLUSIONS This study demonstrates that in nearly 3/5 patients without a definitive diagnosis after routine EEG, SVEM allowed us to reach a diagnosis. This procedure should be encouraged in this setting, given its time-effectiveness compared with LVEM.

PTPN11 mutation manifesting as LEOPARD syndrome associated with hypertrophic plexi and neuropathic pain.

BackgroundLEOPARD syndrome (LS) belongs to the family of neuro-cardio-facio-cutaneous syndromes, which include Neurofibromatosis-1 (NF1), Noonan syndrome, Costello Syndrome, cardio-facio-cutaneous syndrome, Noonan-like syndrome with loose anagen hair and Legius syndrome. These conditions are caused by mutations in genes encoding proteins involved in the RAS-MAPK cellular pathway. Clinical heterogeneity and phenotype overlaps across those different syndromes is already recognized.Case presentationWe hereby report a heterozygous de novo mutation in the PTPN11 gene (c.1403C > T) manifesting with a clinical picture of LS during childhood, and later development of neuropathic pain with hypertrophic plexi, which are typically observed in NF1 but have not been reported in LS.ConclusionLS caused by PTPN11 mutations may be associated with hypertrophic roots and plexi. Consequently, clinicians should be aware of the possible development of neuropathic pain and consider specific diagnostic work-up and management.

Cortical origin of functional recovery in the somatosensory cortex of the adult mouse after thalamic lesion.

To study the degree and time course of the functional recovery in the somatosensory cortex (SI) after an excitotoxic lesion in the adult mouse thalamus, metabolic activity was determined in SI at various times points post‐lesion. Immediately after the lesion, metabolic activity in the thalamically deafferented part of SI was at its lowest value but increased progressively at subsequent time points. This was seen in all cortical layers; however, layers I and Vb recovered more rapidly than layers II, III, IV, Va and VI. Removal of the mystacial whiskers corresponding to the deafferented area, 5 weeks after cortical recovery, produced a subsequent 32% drop in metabolic activity, demonstrating peripheral sensory activation of this part of the cortex. Tracing experiments revealed that the deafferented cortex did not receive a novel thalamic input but that cortico‐cortical and contralateral barrel cortex projections to this area were reinforced. We conclude that the cortical functional recovery after a thalamic lesion is, at least partially, due to modified cortico‐cortical and callosal projections to the deafferented cortical area.

Restricted left gyrus rectus hemorrhage with unusual frontal syndrome presentation.

and collaborating patient with a Glasgow Coma Scale of 14/15 and no neurological deficit or lateralizing signs. The brain CT scan showed a left inferior frontal sub-arachnoid hemorrhage secondary to an aneurysm rupture from the distal left ca-rotid artery bifurcation (M1; grade: Fisch-er IV, HH3, WFNS2), spread to both syl-vian fissures and in the perimesencephalic cistern, which was associated with a left GR parenchymatous hemorrhage. She was treated by cerebral arteriography with em-bolization of the aneurysm by placement of 3 Guglielmi detachable coils, with an ex-cellent result. There were no complications following this procedure. A bedside neuropsychological assess-ment performed 6 days after symptom on-set showed a preserved orientation to time, place, and person, fluent and informative spontaneous oral expression, very slight word-finding difficulties (Boston Naming Test 15/34) and impairment of verbal cate-gory-specific and literal fluency, maxi-mum name of animals (5) and a word be-ginning with M (3) in 1 min, but preserved comprehension (complex command 4 out of 4 correctly executed). There were also slight verbal memory deficits, and a major behavioral slowdown with lack of initia-tive in action and in language that impact-ed on other cognitive functions as oral cal-culation (prolonged thinking time, loss of her train of thought in the course of calcu- De, r Si ar The study of localized and well-cir-cumscribed brain lesions has contributed greatly to our understanding of the func-tion of single brain areas. The gyrus rectus (GR) is part of Brodmann’s area (BA) 11, which together with BA 10 and BA 47 form the orbito-frontal cortex. Lesions of this region are classically associated with dis-inhibition syndromes even if some reports described very few or no behavioral symp-toms after such lesions [1–3] . Here we re-port the case of a 59-year-old woman who suffered a subarachnoid hemorrhage asso-ciated with a restricted lesion of her left GR, with an unusual frontal syndrome presentation.

Sudden paraplegia due to an anterior spinal artery syndrome during the course of Staphylococcus aureus septicemia.

with no irradiation to the lower limbs. Her doctor noticed no neu-rological deficits and proposed an NSAID gluteal intramuscular injection. The patient noticed no relief but 3 days later developed fever, diarrhea and dyspnea for which she was admitted to the emergency ward of our hospital. On admission, she presented with fever (38

Eml1 loss impairs apical progenitor spindle length and soma shape in the developing cerebral cortex

The ventricular zone (VZ) of the developing cerebral cortex is a pseudostratified epithelium that contains progenitors undergoing precisely regulated divisions at its most apical side, the ventricular lining (VL). Mitotic perturbations can contribute to pathological mechanisms leading to cortical malformations. The HeCo mutant mouse exhibits subcortical band heterotopia (SBH), likely to be initiated by progenitor delamination from the VZ early during corticogenesis. The causes for this are however, currently unknown. Eml1, a microtubule (MT)-associated protein of the EMAP family, is impaired in these mice. We first show that MT dynamics are perturbed in mutant progenitor cells in vitro. These may influence interphase and mitotic MT mechanisms and indeed, centrosome and primary cilia were altered and spindles were found to be abnormally long in HeCo progenitors. Consistently, MT and spindle length regulators were identified in EML1 pulldowns from embryonic brain extracts. Finally, we found that mitotic cell shape is also abnormal in the mutant VZ. These previously unidentified VZ characteristics suggest altered cell constraints which may contribute to cell delamination.