Advancing care for traumatic brain injury: findings from the IMPACT studies and perspectives on future research

Research in traumatic brain injury (TBI) is challenging for several reasons; in particular, the heterogeneity between patients regarding causes, pathophysiology, treatment, and outcome. Advances in basic science have failed to translate into successful clinical treatments, and the evidence underpinning guideline recommendations is weak. Because clinical research has been hampered by non-standardised data collection, restricted multidisciplinary collaboration, and the lack of sensitivity of classification and efficacy analyses, multidisciplinary collaborations are now being fostered. Approaches to deal with heterogeneity have been developed by the IMPACT study group. These approaches can increase statistical power in clinical trials by up to 50% and are also relevant to other heterogeneous neurological diseases, such as stroke and subarachnoid haemorrhage. Rather than trying to limit heterogeneity, we might also be able to exploit it by analysing differences in treatment and outcome between countries and centres in comparative effectiveness research. This approach has great potential to advance care in patients with TBI.

Lancet Neurology Dicember 2013

Axonal Guillain-Barré syndrome: concepts and controversies

Acute motor axonal neuropathy (AMAN) is a pure motor axonal subtype of Guillain-Barré syndrome (GBS) that was identified in the late 1990s. In Asia and Central and South America, it is the major subtype of GBS, seen in 30—65% of patients. AMAN progresses more rapidly and has an earlier peak than demyelinating GBS; tendon reflexes are relatively preserved or even exaggerated, and autonomic dysfunction is rare. One of the main causes is molecular mimicry of human gangliosides by Campylobacter jejuni lipo-oligosaccharides. In addition to axonal degeneration, electrophysiology shows rapidly reversible nerve conduction blockade or slowing, presumably due to pathological changes at the nodes or paranodes. Autoantibodies that bind to GM1 or GD1a gangliosides at the nodes of Ranvier activate complement and disrupt sodium-channel clusters and axoglial junctions, which leads to nerve conduction failure and muscle weakness. Improved understanding of the disease mechanism and pathophysiology might lead to new treatment options and improve the outlook for patients with AMAN.

Lancet Neurology 2013 Dicember

Phenotypic spectrum of probable and genetically-confirmed idiopathic basal ganglia calcification

Idiopathic basal ganglia calcification is characterized by mineral deposits in the brain, an autosomal dominant pattern of inheritance in most cases and genetic heterogeneity. The first causal genes, SLC20A2 and PDGFRB, have recently been reported. Diagnosing idiopathic basal ganglia calcification necessitates the exclusion of other causes, including calcification related to normal ageing, for which no normative data exist. Our objectives were to diagnose accurately and then describe the clinical and radiological characteristics of idiopathic basal ganglia calcification. First, calcifications were evaluated using a visual rating scale on the computerized tomography scans of 600 consecutively hospitalized unselected controls. We determined an age-specific threshold in these control computerized tomography scans as the value of the 99th percentile of the total calcification score within three age categories: <40, 40–60, and >60 years. To study the phenotype of the disease, patients with basal ganglia calcification were recruited from several medical centres. Calcifications that rated below the age-specific threshold using the same scale were excluded, as were patients with differential diagnoses of idiopathic basal ganglia calcification, after an extensive aetiological assessment. Sanger sequencing of SLC20A2 and PDGFRB was performed. In total, 72 patients were diagnosed with idiopathic basal ganglia calcification, 25 of whom bore a mutation in either SLC20A2 (two families, four sporadic cases) or PDGFRB (one family, two sporadic cases). Five mutations were novel. Seventy-one per cent of the patients with idiopathic basal ganglia calcification were symptomatic (mean age of clinical onset: 39 ± 20 years; mean age at last evaluation: 55 ± 19 years). Among them, the most frequent signs were: cognitive impairment (58.8%), psychiatric symptoms (56.9%) and movement disorders (54.9%). Few clinical differences appeared between SLC20A2 and PDGFRB mutation carriers. Radiological analysis revealed that the total calcification scores correlated positively with age in controls and patients, but increased more rapidly with age in patients. The expected total calcification score was greater inSLC20A2 than PDGFRB mutation carriers, beyond the effect of the age alone. No patient with a PDGFRB mutation exhibited a cortical or a vermis calcification. The total calcification score was more severe in symptomatic versus asymptomatic individuals. We provide the first phenotypical description of a case series of patients with idiopathic basal ganglia calcification since the identification of the first causative genes. Clinical and radiological diversity is confirmed, whatever the genetic status. Quantification of calcification is correlated with the symptomatic status, but the location and the severity of the calcifications don’t reflect the whole clinical diversity. Other biomarkers may be helpful in better predicting clinical expression.

Brain 2013 November

Whole-Exome Sequencing Identifies a Variant of the Mitochondrial MT-ND1 Gene Associated with Epileptic Encephalopathy: West Syndrome Evolving to Lennox–Gastaut Syndrome

We describe a West syndrome (WS) patient with unidentified etiology that evolved to Lennox–Gastaut syndrome. The mitochondrial respiratory chain of the patient showed a simple complex I deficiency in fibroblasts. Whole-exome sequencing (WES) uncovered two heterozygous mutations in NDUFV2 gene that were reassigned to a pseudogene. With the WES data, it was possible to obtain whole mitochondrial DNA sequencing and to identify a heteroplasmic variant in the MT-ND1 (MTND1) gene (m.3946G>A, p.E214K). The expression of the gene in patient fibroblasts was not affected but the protein level was significantly reduced, suggesting that protein stability was affected by this mutation. The lower protein level also affected assembly of complex I and supercomplexes (I/III₂/IV and I/III₂), leading to complex I deficiency. While ATP levels at steady state under stress conditions were not affected, the amount of ROS produced by complex I was significantly increased.

Human Mutation November 2013

Transient compartment-like syndrome and normokalaemic periodic paralysis due to a Cav1.1 mutation

We studied a two-generation family presenting with conditions that included progressive permanent weakness, myopathic myopathy, exercise-induced contracture before normokalaemic periodic paralysis or, if localized to the tibial anterior muscle group, transient compartment-like syndrome (painful acute oedema with neuronal compression and drop foot). ²³Na and ¹H magnetic resonance imaging displayed myoplasmic sodium overload, and oedema. We identified a novel familial Ca_v1.1 calcium channel mutation, R1242G, localized to the third positive charge of the domain IV voltage sensor. Functional expression of R1242G in the muscular dysgenesis mouse cell line GLT revealed a 28% reduced central pore inward current and a −20 mV shift of the steady-state inactivation curve. Both changes may be at least partially explained by an outward omega (gating pore) current at positive potentials. Moreover, this outward omega current of 27.5 nS/nF may cause the reduction of the overshoot by 13 mV and slowing of the upstroke of action potentials by 36% that are associated with muscle hypoexcitability (permanent weakness and myopathic myopathy). In addition to the outward omega current, we identified an inward omega pore current of 95 nS/nF at negative membrane potentials after long depolarizing pulses that shifts the R1242G residue above the omega pore constriction. A simulation reveals that the inward current might depolarize the fibre sufficiently to trigger calcium release in the absence of an action potential and therefore cause an electrically silent depolarization-induced muscle contracture. Additionally, evidence of the inward current can be found in ²³Na magnetic resonance imaging-detected sodium accumulation and ¹H magnetic resonance imaging-detected oedema. We hypothesize that the episodes are normokalaemic because of depolarization-induced compensatory outward potassium flux through both delayed rectifiers and omega pore. We conclude that the position of the R1242G residue before elicitation of the omega current is decisive for its conductance: if the residue is located below the gating pore as in the resting state then outward currents are observed; if the residue is above the gating pore because of depolarization, as in the inactivated state, then inward currents are observed. This study shows for the first time that functional characterization of omega pore currents is possible using a cultured cell line expressing mutant Ca_v1.1 channels. Likewise, it is the first calcium channel mutation for complicated normokalaemic periodic paralysis

Brain 2013 November

Mitochondrial DNA Rearrangements in Health and Disease—A Comprehensive Study

Mitochondrial DNA (mtDNA) rearrangements cause a wide variety of highly debilitating and often fatal disorders and have been implicated in aging and age-associated disease. Here, we present a meta-analytical study of mtDNA deletions (n = 730) and partial duplications (n = 37) using information from more than 300 studies published over the last 30 years. We show that both classes of mtDNA rearrangements are unequally distributed among disorders and their breakpoints have different genomic locations. We also demonstrate that 100% of cases with sporadic mtDNA deletions and 97.3% with duplications have no breakpoints in the 16,071 breakage hotspot site, in contrast with deletions from healthy and aged tissues. Notably, most deletions removing a section of the D-loop are found in tumors. Deleted mtDNA molecules lacking the origin of L-strand replication (O_L) represent only 9.5% of all reported cases, whereas extra origins of replication occur in all duplications. As previously shown for deletions, imperfect stretches of homology are common in duplication breakpoints. Finally, we provide a dedicated Website with detailed information on deleted/duplicated mtDNA regions to facilitate the design of efficient methods for identification and screening of rearranged mitochondrial genomes 

Human Mutation November 2013

Assessment of system dysfunction in the brain through MRI-based connectomics

Network-based analysis of structural and functional connections has provided a new technique to study the brains of healthy people and patients with neurological and psychiatric disorders. Graph theory provides a powerful method to quantitatively describe the topological organisation of brain connectivity. With such a framework, the brain can be depicted as a set of nodes connected by edges. Distinct modifications of network topological organisation in the brain have been identified during development and normal ageing, whereas disrupted functional and structural connectivities have been associated with several neurological and psychiatric disorders, including dementia, amyotrophic lateral sclerosis, multiple sclerosis, and schizophrenia. These assessments have improved understanding of the clinical manifestations noted in these patients, including disability and cognitive impairment. Future network-based research might enable indentification of different stages of disorders, subtypes for cognitive impairment, and connectivity profiles associated with different clinical outcomes.

Lancet Neurology November 2013